Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([CH:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=O)[CH2:17]/[C:18](=[N:20]/[N:21]([C:23](OC(C)(C)C)=O)C)/[CH3:19])=[CH:15][C:10]=2[CH2:9][CH2:8][N:7](C([O-])=O)[CH2:6]1)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][N:21]1[C:16]([C:14]2[CH:13]=[CH:12][C:11]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=3[CH:15]=2)=[CH:17][C:18]([CH3:19])=[N:20]1
Reactant: C/C(CC(=O)c1ccc2c(c1)CCN(C(=O)[O-])CC2C(C)(C)C)=N\N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Yield: 98.8 %

Procedure:
A solution of 1,1-dimethylethyl-7-{(3E)-3-[{[(1,1 dimethylethyl)oxy]carbonyl}(methyl)hydrazono]butanoyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.5 g) (intermediate 2) in dichloromethane (5 ml) was added dropwise to trifluoroacetic acid (10 ml) under vigorous stirring. After 1 h the reaction mixture was concentrated in vacuo and sodium hydroxide (1N) was added until pH ˜12, then the mixture was extracted twice with dichloromethane. The organic phase was dried with sodium sulphate and evaporated to give the title compound (0.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-(aminomethyl)pyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-ylmethyl)terephthalamide. MS (Q1) 477 (M)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]=[CH:4][C:5]#[N:6].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCOCC1>[CH3:1][N:2]([CH3:7])[CH:3]=[C:4]([C:18](=[O:19])[C:17]1[CH:21]=[C:22]([F:26])[C:23]([Cl:25])=[CH:24][C:16]=1[Cl:15])[C:5]#[N:6]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: CN(C)C=CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C=C(C#N)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 77.4 %

Procedure:
9.6 g of 3-dimethylaminoacrylonitrile and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 1 hour and then heated to boiling under reflux for 4 hours. The solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The methylene chloride phase is washed with water, dried with sodium sulphate, and evaporated in vacuo. The crystalline residue is recrystallized from ethanol. 22.2 g of 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylonitrile of melting point 138°-139° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[H][H]>CO.[C].[Pd]>[CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
1.77 g of N-methyl-1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 30 ml of methanol. Then, 200 mg of 10% palladium carbon was added to the obtained solution. The reaction atmosphere was replaced by hydrogen, and it was then stirred at room temperature. After completion of the reaction, 10% palladium carbon was filtered off from the reaction solution, and the reaction solution was then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), followed by solidification from a mixed solution consisting of ethyl acetate, t-butylmethyl ether, and methanol, so as to obtain 973 mg of the subject compound.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6][C:5]1=[O:15])([CH3:3])[CH3:2].[OH-].[Na+].[Br:18]Br.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([Br:18])=[C:7]([C:11]([F:12])([F:14])[F:13])[NH:6][C:5]1=[O:15])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(=O)[nH]c(C(F)(F)F)c(Br)c1=O

Procedure:
3-isopropyl-6-(trifluoromethyl)uracil as prepared in Example 1 (7.4 g., 0.033 mole) was dissolved in a mixture of 0.5N NaOH (0.04 mole) and chloroform (15 ml.). A solution of bromine (5.89 g., .036 mole) in 25 ml. chloroform was added in portions with stirring. After the addition was complete, the reaction mixture was stirred for one-half hour before discharging the bromine color with sodium bisulfite. The layers were separated, and the aqueous layer extracted with fresh chloroform. The combined chloroform extracts were washed with water and then evaporated to dryness leaving 10.1 g. (100%) of white solid residue. One recrystallization from benzene gave a product with a melting point of 146°-150°C. The analytical sample melted at 149°-150°C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C1(C)C(C)=CC=CC=1>[CH3:15][O:16][CH2:17][C:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]=1
Reactant: COCC(=O)NCCc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COCC1=NCCc2ccccc21

Procedure:
Phosphorous pentoxide (25 g, 0.176 mol) was added to a stirred solution of the product from (a) above (14.47 g, 0.075 mol) in xylene (35 ml) and the resulting mixture heated under reflux for 2.5 hours. The solvent was decanted from the resulting black gum which was triturated with xylene and then, when cool, with ether. Water was then carefully added, with ice-cooling, and the resulting mixture basified with 2M aqueous sodium hydroxide solution and then extracted with ether. The extract was washed with water, dried (MgSO4) and evaporated under reduced pressure to give a brown oil (13.4 g) which was purified by chromatography on silica gel, using ether as eluant, to afford the required compound (5.88 g) as an orange oil. Rf 0.28 (SS 2).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)([CH3:7])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.CCN(CC)CC>C1C=CC=CC=1>[Cl:15][C:10]1[CH:9]=[C:8]([C:5]([C:4]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[C:25]([SH:26])=[N:2][CH:3]=2)([CH3:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CC(C)(C(=O)CN)c1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of 1-amino-3-(3,4-dichlorophenyl)-3-methylbutan-2-one hydrobromide (900 mg, 2.75 mmol), 4-fluorophenyl isothiocyanate (464 mg, 3.029 mmol), and Et3N (570 uL, 4.13 mmol) in dry benzene (20 mL) was heated at reflux 6 h. The reaction mixture was concentrated under reduced pressure, diluted with acetic acid (9 mL) and then heated at reflux 5 h. After cooling to room temperature and concentrating, the crude product was purified by flash column chromatography to afford 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (370 mg). 1H NMR (400 MHz, CDCl3) δ 7.15 (m, 2H), 6.91 (m, 2H), 6.80 (m, 2H), 6.62 (m, 2H), 1.61 (s, 6H).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NC(CO)CO
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(CO)CO)cn1
Yield: 30 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using 2-amino-1,3-propanediol instead of rac-2-amino-1-propanol, to the title compound (53 mg, 30%) which was obtained as a white solid after purification by chromatography (silica, 0 to 8% methanol in dichloromethane). MS: m/e=364.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[I:17])[C:10](=[O:18])[O:9]1)([CH3:6])[CH2:3][S:4][CH3:5].[CH3:19][C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][C:39]=1[NH2:40])[CH2:23][N:24]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([C:33]([F:36])([F:35])[F:34])=[N:25]1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:36][C:33]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([C:29]([F:32])([F:30])[F:31])[N:24]([CH2:23][C:22]2[CH:37]=[CH:38][C:39]([NH:40][C:10](=[O:18])[C:11]3[C:16](=[C:15]([I:17])[CH:14]=[CH:13][CH:12]=3)[C:8]([NH:7][C:2]([CH3:6])([CH3:1])[CH2:3][S:4][CH3:5])=[O:9])=[C:20]([CH3:19])[CH:21]=2)[N:25]=1
Reactant: CSCC(C)(C)N=C1OC(=O)c2cccc(I)c21
Reactant: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)cc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-(1,1-Dimethyl-2-methylsulfanyl-ethylimino)-4-iodo-3H-isobenzofuran-1-one (0.53 g) and 1-(3-methyl-4-aminobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (0.45 g) were dissolved in acetonitrile (15 ml), to which p-toluenesulfonic acid monohydrate (0.01 g) was added and the mixture was stirred at 60° C. for 3 hours. After finishing the reaction, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-methylphenyl]-N2-(1,1-dimethyl-2-methylsulfanylethyl)-3-iodophthalamide (0.91 g). mp. 83-87° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH2:4][CH2:3]1.O.NN>C(O)C.[Ni].O>[CH3:18][O:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1N1CCN(C)CC1
Yield: 53 %

Procedure:
To a solution of the product of step (a) (5.07 g) in ethanol (70 ml) was added a paste of Raney Nickel in water (2 g). To the warmed suspension was added, with constant agitation, hydrazine hydrate (5 ml) dropwise during 20 min with occasional warming. After the main effervescence had ceased, the suspension was heated for 15 min and then filtered with the aid of ethanol under nitrogen. The residues were kept moist and washed with ethanol and the combined filtrate and washings were evaporated to dryness with the aid of ethanol. The dark residue was re-evaporated with ethanol (20 ml), resuspended in ether (40 ml) and the mixture filtered. The residue was washed with ether and dried to give a solid consisting of the title compound (2.365 g) T.l.c System A (70:8:1), Rf 0.25.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([N:10]1[CH2:34][CH2:33][CH2:32][C@H:11]1[C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[OH:19])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[C:35](Cl)(=[O:37])[CH3:36].N1C=CC=CC=1>O1CCCC1>[NH:1]([C:35]([CH3:36])=[O:37])[C@H:2]([C:8]([N:10]1[CH2:34][CH2:33][CH2:32][C@H:11]1[C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:16][CH2:17][C:18](=[O:19])[OH:20])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 12 h

Procedure:
A mixture of 500 mg of Gln-Pro-Glu-Asn, 0.7 ml of acetyl choride, 0.5 ml of pyridine and 10 ml of tetrahydrofuran is kept at 20° for 12 hours. The mixture is evaporated, the residue is purified by means of TLC to yield Ac-Gln-Pro-Glu-Asn.
Reaction SMILES: [NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([OH:5])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:5]
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)NCCC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ac-Gly-OH a (3.77 g, 32.2 mmol) and triethylamine (6.7 mL, 48.1 mmol) were dissolved in 160 mL THF and cooled to −10° C., and isobutylchloroformate (5.02 g, 38.6 mmol) was added. The mixture was stirred at −10° C. for 1 hr. H-beta-Ala-OBzl.PTSA e (11.26 g, 32.0 mmol) and triethylamine (6.7 mL, 48.1 mmol) was dissolved in 160 mL THF, and added into mix anhydride solution. The reaction mixture was stirred at room temperature overnight. The salt was filtrated off and THF was removed in vacuum. The residue obtained was purified by column chromatography using ethyl acetate and heptane as eluent to obtain 5.95 g Ac-Gly-beta-Ala-OBzl f.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13]C)[C:10]([CH3:12])([CH3:11])O2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:10]([CH3:11])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: COC1(c2ccc(F)cc2)OC1(C)C
Reactant: C1COCCN1
Product: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Temperature: 130 °C

Procedure:
29.43 g (0.15 mol) of 2-(4-fluorophenyl)-3,3-dimethyl-2-methoxyoxirane and 52.3 g (0.60 mol) of morpholine are brought together, and the mixture is heated to reflux temperature (about 130° C.). After 23 hours the excess morpholine is distilled off. The residue is taken up with toluene, and the mixture is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and is concentrated. The residue, 34.0 g, crystallises out from ethyl acetate with a melting point of 63°-66° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:33]([CH3:40])[CH3:32])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Reactant: CN(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
To a stirred DCM (15 mL) solution of the product from Example 1 (58 mg), 4-(dimethylamino)butyric acid hydrochloride (28.2 mg) and TEA (0.059 mL) was added HATU, (58.7 mg) under nitrogen. The resulting solution was stirred at rt for 16 h. The solvent was evaporated and the residue was taken up in MeOH and the crude product purified by RPHPLC to afford the title compound 5 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13].[I-:14].[Na+].CN(C)CCN(C)C>[Cu](I)I>[I:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13]
Reactant: [I-]
Reactant: Cc1cc(O)cc2cc(Br)cnc12
Agent: I[Cu]I
Agent: CN(C)CCN(C)C
Agent: [Na+]
Product: Cc1cc(O)cc2cc(I)cnc12

Procedure:
In a similar procedure to Step 1 of Example 13A, 3-bromo-8-methyl-quinolin-6-ol (preparation described in Example 13 Stage 1) was reacted sodium iodide, copper iodide and N,N,N′,N′-tetramethyl-ethane-1,2-diamine to give the required product, 3-iodo-8-methyl-quinolin-6-ol, as a brown coloured solid (MH+ 286).
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([C:13](N[C@H](C(NC(C=O)CC(O)=O)=O)C)=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-].C[OH:31]>>[CH2:1]([C:8]1[NH:12][C:11]([C:13]([OH:14])=[O:31])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: C[C@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)NC(C=O)CC(=O)O
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc(Cc2ccccc2)[nH]1

Procedure:
3-[N-(5-Benzylpyrrole-2-carbonyl)-L-alaninyl]amino-4-oxobutanoic acid (36b), was prepared (41%) from 35b by the method described for compound 36a, to afford an off white solid: mp. 109-112° C.; [α]D25 +6.3° (c 0.3, methanol); IR (KBr) 3368, 1724, 1630, 1530, 1453, 1414, 1233, 1049; 1H NMR(d4 methanol) δ 7.25-7.11 (5H, m), 6.76 (1H, d, J=3.5), 5.84 (1H, d, J=3.5), 4.51 (1H, m), 4.43 (1H, q, J=7.1), 4.23 (1H, m), 2.5 (2H, m),1.35 (3H, d, J=7.0). Anal. Calcd for C19H21N3O5. 1.75H2O: C, 56.64; H, 6.13; N, 10.43. Found: C, 56.34; H, 5.72; N, 10.00.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH:12][C:13](=O)[CH2:14][Cl:15])=[C:4]([F:17])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>ClCCCl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]=[C:13]([Cl:38])[CH2:14][Cl:15])=[C:4]([F:17])[CH:3]=1
Reactant: C#CCOc1cc(NC(=O)CCl)c(F)cc1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: C#CCOc1cc(N=C(Cl)CCl)c(F)cc1Cl
Reaction time: 2 h

Procedure:
First, 2.00 g of N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-chloroacetamide, 4.50 g of triphenylphosphine and 5 ml of carbon tetrachloride were dissolved in 45 ml of 1,2-dichloroethane, and then the reflux under heat was continued for 2 hr. After letting the solution stand to cool the same, the solvent was distilled out under reduced pressure, and then the residue was refined by silica gel column chromatography (effluent: ethyl acetate/n-hexane (v/v)=6/4) to obtain 1.43 g of N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-chloroacetimidoylchloride. The boiling point was 144°-146° C./0.4 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([Br:26])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cccnc2N)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-(2-aminopyridin-3-yl)-2-methylbenzoate (4.2 g, 17.34 mmol) in acetonitrile (173 mL) was added NBS (3.15 g, 17.68 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. LCMS showed the reaction completed. After quenched with sat. Na2SO3 and NaHCO3, the reaction mixture was stirred for 30 min. The reaction mixture was extracted with EtOAc 3 times, washed by sat NaHCO3, water and brine. The organics was dried over Na2SO4, filtered and concentrated. The crude material was triturated with ether and taken to the next step without further purification. LCMS (m/z): 323.1 (MH+), 0.68 min.
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][N:29]=3)=O)[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][N:29]=3)=[S:49])[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH:11]2
Reactant: O=C(c1ncc(-c2ccncc2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=S)c2ncc(-c3ccncc3)cn2)CC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a mixed solvent of dimethoxyethane (10 ml) and toluene (10 ml) was suspended 1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine (100 mg) at room temperature, followed by the addition of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 42 mg). The resulting mixture was heated under reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by chromatography on a silica gel column (3→5% methanol—methylene chloride). 1N hydrochloric acid (in ethanol) was added to make acidic the purified product. After concentration, ethyl acetate was added. Yellow powder so precipitated was collected by filtration and dried, whereby the title compound (34 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18](Cl)=[N:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a suspension of sodium hydride (5.08 g, 127 mmol) in N,N-dimethylformamide (75 mL) was added diethyl malonate (19.26 mL, 127 mmol) at 0° C. The solution was then stirred at ambient temperature for 30 minutes and a solution of 5-bromo-2-chloro-3-nitropyridine (30 g, 127 mmol) in N,N-dimethylformamide (75 mL) was added dropwise. The dark brown mixture was then stirred at 100° C. for 2 hours before being cooled to ambient temperature and quenched with a saturated solution of ammonium chloride (500 mL) at 0° C. The mixture was extracted with ethyl acetate (3×500 mL) and the combined organics were dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give a dark brown oil which was purified by flash column chromatography (10% ethyl acetate/hexane) to afford diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate as a brown solid (31.8 g, 69%). 1HNMR (400 MHz, CDCl3, δ): 8.86 (s, 1H), 8.61 (s, 1H), 5.44 (s, 1H), 4.29 (q, 4H), 1.27 (t, 6H).