Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:8])[N:4]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Fluorocytosine (500 mg) and potassium carbonate (803 mg) were suspended in N,N-dimethylformamide (5 mL) and ethyl bromoacetate (430 μL) was added to the suspension. The mixture was stirred at 100° C. overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=99:1 to 92:9) to give 329 mg (39% yield) of the desired product as a white amorphous.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.F[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1>O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of 4-methoxyphenol (2.4 g). The reaction mixture was stirred at room temperature for 5 minutes, to which was added 4-fluorobenzenecarbonitrile (2.4 g). The reaction mixture was stirred at room temperature for 4 hours, which was further stirred at 50° C. for one hour. The reaction mixture was poured into water, which was extracted with toluene. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1), and then recrystallized from toluene-hexane to obtain 4-[(4-methoxyphenyl)oxy]benzenecarbonitrile (2.0 g).
Reaction SMILES: [C:1](=[S:6])([O:3]CC)[NH2:2].Br[CH2:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O>O1CCOCC1>[CH2:15]([O:14][C:12]([C:11]1[S:6][C:1](=[O:3])[NH:2][C:9]=1[CH3:8])=[O:13])[CH3:16]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: CCOC(N)=S
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(=O)[nH]c1C

Procedure:
84 g of ethyl thiocarbamate were added to 500 ml of dioxane and then 168 g of ethyl α-bromoacetylacetate was added thereto dropwise. The mixture was refluxed for 4 hours and the solvent was then evaporated under reduced pressure. The solid residue was crystallized from benzene to obtain 72g of 5-ethoxycarbonyl-4-methyl-4-thiazoline-2-one in the form of white crystals melting at 172°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]([CH:14]1[CH2:16][CH2:15]1)([CH3:13])[CH3:12])C(OCC)=O)[CH3:2].[Li+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:11]([CH:14]1[CH2:15][CH2:16]1)([CH3:12])[CH3:13])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(C)(C)C1CC1
Temperature: 170 °C
Yield: 66 %

Procedure:
Step B To a solution of 2-(1-cyclopropyl-1-methyl-ethyl)-malonic acid diethyl ester (4.3 g, 17.8 mmol) in DMSO (30 mL) was added LiCl (1.5 g, 35.6 mmol) and H2O (0.3 mL, 17.8 mmol). The reaction mixture was heated at 170° C. for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-cyclopropyl-3-methyl-butyric acid ethyl ester as a colorless oil (2 g, 66%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.[Mg].O1CCOC1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>O1CCCC1>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC(C)(C)C=O
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: C1COCO1
Product: CC1(c2ccc(C(O)C(C)(C)C)cc2)OCCO1
Reaction time: 8 h

Procedure:
In 250 milliliters of tetrahydrofuran, 118 grams of the above dioxolane is dissolved. One quarter of this solution is then added to 12 grams of magnesium previously washed with chloroform, and refluxed with tetrahydrofuran for 20 minutes; and this mixture is refluxed 4 hours to initiate reaction. Additional dioxolane solution is thereafter added to maintain the refluxing without further heating. After the addition has been completed, 35 grams of 2,2-dimethylpropanal is added and the mixture is refluxed for 2 hours. The reactants are allowed to stand overnight and then poured onto ice-cold ammonium chloride solution. Tetrahydrofuran is added and the two layers formed are allowed to separate. The solvent layer is decanted off and the aqueous layer is extracted twice with 100 milliliters of tetrahydrofuran which are decanted off and combined with the remaining solvent layer. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which is distilled at 120° to 150°C. at 30M and recrystallized from pentane/ether to yield 2-methyl- 2-(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane (m.p. 75°-80°C.).
Reaction SMILES: [C:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH2:21][Br:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)c1ccccc1n2C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c2ccccc2c2cc(CBr)ccc21
Yield: 80 %

Procedure:
To a stirred solution of N-Boc 3-Methylcarbazole (85 mg, 0.3 mmol) and N-bromo succinimide (54 mg, 0.3 mmol) in carbon tetrachloride (10 mL) was added benzoyl peroxide (10 mg), and the reaction was heated at reflux for about 12 h. The cooled reaction mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was purified using column chromatography on silica gel with hexane/ethyl acetate as eluant (86 mg, 80% yield). ES-MS (M-Br)+ 280.9 (calc. 280.15).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])(C)(C)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:28](=[O:27])[CH2:29][C:30]([C:32]4[S:33][C:34]([Cl:37])=[CH:35][CH:36]=4)=[O:31])[CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: CCCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)CC(=O)c1ccc(Cl)s1

Procedure:
The titled compound is prepared by a modification of a procedure published by Witzeman and Nottingham. (J. Org. Chem. 1991, 56, 1713.). 1-(4-Aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one (0.299 g, 1 mmol) and 3-(5-chloro-thiophen-2-yl)-3-oxo-propionic acid tert-butyl ester (0.287 g, 1.1 mmol) are dissolved in 10 ml of pyridine. The flask containing the resulting solution is placed in an oil bath preheated to 125° C. The reaction is heated with stirring under a stream of nitrogen gas for one hour until most of the pyridine had evaporated. The remaining pyridine is evaporated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% CH3OH/H2CCl2 to 10% CH3OH/H2CCl2 to provide the product (0.48 g, 0.98 mmol). The product could be recrystallized from CH2Cl2/hexane to yield a yellow solid. M.P. 120-5° C. (dec). MS (ion spray) m/z 486, (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)[S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-:22])=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Na+].C(Cl)(=O)C(Cl)=O.Cl.[CH3:45][O:46][NH2:47].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:45][O:46][NH:47][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([S:13]([N:12]([C:3]2[N:4]=[CH:5][C:6]3[C:11]([C:2]=2[CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=2)(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)ncc2ccccc12
Reactant: CON
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CONC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a suspension of sodium 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (107.7 mg, 0.200 mmol) prepared in Example 2 in chloroform (1 mL) was added oxalyl dichloride (21 μL, 0.240 mmol), and the mixture was stirred at room temperature for 2 hours. Then, thereto was added additional oxalyl dichloride (21 μL, 0.24 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was suspended in chloroform (1 mL), and added dropwise to a suspension of O-methylhydroxylamine hydrochloride (50.1 mg, 0.600 mmol) and triethylamine (139 μL, 1.00 mmol) in chloroform (1 mL), and the mixture was stirred at room temperature for 1 hour. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→0:10) to give N-methoxy-4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzamide (88.1 mg, 81%) as a white powder.
Reaction SMILES: C(C1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[C:5]([F:16])[CH:4]=1)#N.C1COCC1.CO.[OH-].[Na+].CC[O:28][C:29]([CH3:31])=[O:30]>>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7]([C:6]1[CH:14]=[CH:15][C:31]([C:29]([OH:28])=[O:30])=[CH:4][C:5]=1[F:16])=[O:8])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(C#N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(=O)O)cc1F
Temperature: 65 °C
Yield: 66 %

Procedure:
To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) at room temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol) followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g, 5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc and washed with brine solution. The organics were separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc-DCM (10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H), 7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24 (td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75 g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4 N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heated at 65° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc and washed with 2 M HCl solution. The organics were separated, dried and concentrated in vacuo to give 4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid. ESI-MS m/z calc. 239.24. Found 240.2 (M+1); Retention time: 0.99 minutes (3 min run).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:9])=[O:8])=[C:11]([F:30])[CH:12]=2)=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 71.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (210 mg, 0.350 mmol) prepared in Example 37b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (113 mg, 72%) as a colorless solid.
Reaction SMILES: O1CCCC1.[OH:6][CH:7]([C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)[CH3:8].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>O>[Si:18]([O:6][CH:7]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)[CH3:8])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1nc2ccccc2[nH]1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 50 ml of tetrahydrofuran containing 2.5 g (15.4 mmoles) of 1-hydroxyethylbenzimidazole, 2.3 g (15.4 mmoles) of t-butyldimethylsilyl chloride and 1.0 g (15.4 mmoles) of imidazole was allowed to stir overnight at room temperature. The reaction mixture was poured into water and the product extracted with ethyl acetate (2×100 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to a colorless oil, 3.5 g. The intermediate was purified by chromatography on 100 g of silica gel using chloroform as the eluent, 3.11 g.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([OH:13])=[C:5]2[C:4]1=[O:19])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:13][CH3:20])=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(CC)C[C@@H]2C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn2c(c1OC)C(=O)N(CC)C[C@@H]2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (4S)-2-ethyl-8-hydroxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (6.6 g, 24.8 mmol), anhydrous potassium carbonate (13.7 g, 99.1 mmol, 325 mesh), and iodomethane (4.2 g, 29.7 mmol) in anhydrous DMF (123 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-3% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound. Residual methanol was removed by concentrating from its solution in toluene under vacuum.
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][N:11]1[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[N:12]1.[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:28]2=[O:39])[S:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])[C:28]2=[O:39])[S:22][C:23]=1[C:24]([NH:17][CH2:16][C:14]1[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=1)=[O:25]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 49 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (1-methyl-1H-pyrazol-4-yl)methanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 49% yield: 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.37 (s, 1H), 5.79-5.76 (m, 1H), 4.40 (d, J=5.3 Hz, 2H), 4.15-4.09 (m, 2H), 3.87 (s, 3H), 3.62-3.57 (m, 2H), 3.42-3.37 (m, 2H), 2.60 (s, 3H), 2.19-2.11 (m, 2H), 1.88-1.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.1, 155.6, 152.8, 138.7, 129.4, 118.2, 117.4, 42.9, 42.3, 42.0, 38.9, 34.4, 31.4, 30.9, 20.2, 17.2; MS (ES+) m/z 430.9 (M+1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@@H:32]([C:39]([NH2:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O1CCOCC1.Cl.SC(O)C>CCOCC>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@@H:32]([C:39]([NH2:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: CC(O)S
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 7.7 %

Procedure:
6.0 g (88.8 mmoles) of BOC-Trp-Met-Asp-D-Phg-NH2, prepared as described in Example 1, Step 7, are treated with 60 ml of a dioxane solution of hydrochloric acid in the presence of 3.1 ml (44 mmoles) of mercaptoethanol. After 15 minutes the reaction mixture is diluted with dry ether, and the separated solids are filtered off. The resulting 6.23 g. of hydrochloride, containing a large excess of hydrochloric acid, is suspended in 150 ml of water, the suspension is neutralized (pH=7) with triethylamine, stirred, and the precipitate is filtered off and washed with water. 4.0 g (78%) of H-Trp-Met-Asp-D-Phg-NH2 are obtained; m.p.: 230°-232° C. (decomposition); Rf7 =0.3.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:32]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:33])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)N2CCOCC2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL flask, 3-aminomethyl-7-chloro-1-phenyl-1H-quinolin-4-one hydrochloride salt (intermediate I) (50 mg, 0.132 mmol) and morpholine-4-carbonyl chloride (21.7 mg, 0.145 mmol) were combined with CH2Cl2 (5 mL) and stirred at 0° C. for 10 min. Then N,N-diisopropylethylamine was added at 0° C. over 1 hr. The reaction mixture was stirred at and stirred at 0° C. for 4 hr. The reaction mixture was concentrated. The crude product was purified using preparative reverse phase HPLC to yield the product 7-chloro-3-{[(morpholine-4-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester. MS calcd. for C23H23ClN3O5 [(M+H)+] 456.1, obsd. 455.9.
Reaction SMILES: C[O:2][C:3]1[CH:36]=[CH:35][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][C:11]([O:18]C)=[CH:12][CH:13]=1)[CH:8]3[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCCl>[OH:2][C:3]1[CH:36]=[CH:35][C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=1)[C:14]1[C:9](=[CH:10][C:11]([OH:18])=[CH:12][CH:13]=1)[CH:8]3[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:25]=1
Reactant: COc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: Oc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(O)ccc12

Procedure:
One g of the compound of Example 11 was added to 1.9 g of aluminum chloride and 1.3 g of ethanethiol in 25 ml of 1,2-dichloroethane and the reaction was carried out and the product isolated as described in Example 14. One g of impure oily product was obtained, which was purified by Waters Prep 500 liquid chromatography over normal phase silica gel, using a gradient solvent which began with 2% methanol in chloroform and progressed to 30% methanol in chloroform. The product-containing fractions were evaporated to dryness under vacuum to obtain 0.7 g of the desired product as a tan foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Yield: 79.4 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylamino-benzothiazol-6-yl ester (intermediate 15) (1 g, 2.32 mmol), isobutylamine (517 mg, 7.07 mmol) and cesium carbonate (845 mg, 2.59 mmol) in 12 ml of DMSO is stirred at 80° C. overnight. 60 ml of water are added to the reaction medium. The mixture is extracted with ethyl acetate. The organic phase is washed with water and with saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The residue is washed with ethyl ether to give 880 mg of 4-isobutylaminobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (beige-colored solid) in a yield of 80%.