Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N+:9]([O-:29])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C1CCN=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CC[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6.4 g (22 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of m-chloroperbenzoic acid in 350 ml of methylene chloride was stirred at room temperature for 2 hr. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The oil was crystallized from a mixture of ether and petroleum ether to give off-white prisms, mp 166°-168° C. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 168°-170° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/c2cccc([N+](=O)[O-])c2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(/C=C/c2cccc(N)c2)cn1
Yield: 89.5 %

Procedure:
A mixture of 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]nitrobenzene (3.0 g), iron powder (1.48 g) and ammonium chloride (0.57 g), ethanol (30 ml) and water (9 ml) was stirred under reflux for 5 hours. The reaction was filtered, concentrated and extracted with chloroform. The extracts were chromatographed on silica gel (20 g, chloroform-methanol 100:1 as eluent) to give an oil. Crystallization from methanol afforded 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]aniline (2.4 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[O:9][CH3:10].[NH2:13][CH2:14][C@@H:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:19][CH2:18][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:16]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:28]([N:17]1[CH2:18][CH2:19][C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C@@H:15]([CH2:14][NH:13][C:8](=[O:11])[O:9][CH3:10])[CH2:16]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)NC[C@H]1CN(Cc2ccccc2)CC[C@@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
111 μL of triethylamine and 37 μL of methyl chlorocarbonate were added to chloroform (2 mL) solution of 93 mg of (3S*,4S*)-3-aminomethyl-1-benzyl-4-o-tolyl-piperidine obtained in Production Example 37, and stirred at room temperature for 50 minutes. Aqueous 1 M sodium hydroxide solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 78 mg of the entitled compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:3])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: Nc1cccnc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)Nc3cccnc3)coc12
Yield: 19 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and 3-aminopyridine (0.088 g) to give Compound 156 (0.068 g, 19%) as white crystals.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]1=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of ethyl 3,4-dihydro-3-oxo-2-quinoxalinecarboxylate (4.4 g) under ice-cooling. The reaction mixture was stirred for 10 minutes, to which was added benzyl bromide (2.4 g). The reaction mixture was stirred at room temperature for 3 hours, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (3.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35]C)(=[O:33])C>CO>[CH3:35][O:34][C:31]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:10][O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:23]=1)=[O:33]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COCc2ccc(Br)cc21
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)COC2
Yield: 43 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (2.00 g, 4.78 mmol), triethylamine (1.21 g, 11.9 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (200 mg, 0.239 mmol) in methanol (30 mL) and ethyl acetate (30 mL) was heated at 130° C. under a carbon monoxide atmosphere (100 bar) for 3 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to produce 1-(5-chloro-2-methoxybenzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylic acid methyl ester (825 mg, 43%). Orange solid, MS (ISP)=398.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(Nc3ccccc3)nc(Cl)nc12

Procedure:
A solution of 2,4-dichloro-8-methoxy-quinazoline (prepared as described in J. Chem. Soc. 1948, 1759) (0.6 g), N,N-diisopropyl-ethylamine (0.87 ml), and aniline (0.26 ml) in isopropanol (10 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and residue is crystallized from dichloromethane and hexanes to give 2-chloro-8-methoxy-4-phenylamino-quinazoline, m.p. 245-246° C.
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:46])[C@@H:15]([NH:28]C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.N1CCOCC1>CN(C=O)C>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:46])[C@@H:15]([NH2:28])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: N[C@@H](CCCCOCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 726 mg (S)-4-[6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-piperazine-1-carboxylic acid cyclobutyl ester in 4.0 ml DMF were added at room temperature 1.0 ml morpholine. After stirring for 2 h the reaction mixture was evaporated and the crude product thus obtained used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(Cc1nc(CCCCCNc2ccccn2)co1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(Cc1nc(CCCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a solution of ethyl (±)-3-phenyl-4-[4-[5-(pyridin-2-yl)amino- 1-pentyl]-1,3-oxazol-2-yl]butanoate (75 mg, 0.18 mmole) in 1:1 THF/H2O (2 mL) was added 1.0 N LiOH (0.27 mL, 0.27 mmole). After 18 hr, the pH was adjusted to 6 using 10% HCl; then the solution was concentrated under reduced pressure to remove the THF. The solution was chromatographed on a C-18 Mega Bond Elut® column (50 mL H2O then 200 mL 20% CH3CN/H2O containing 0.1% TFA). Fractions containing the product were pooled and lyophilized to give the title compound (43 mg, 61%) as a yellow gum: MS (ES) m/e 394 (M+H)+. Anal. Calcd for C23H27N3O3.0.098 CF3CO2H: C, 68.85; H, 6.75; N, 10.38. Found: C, 69.23; H, 7.00; N, 9.98.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH2:20]([O:22][C:23]([CH2:25]I)=[O:24])[CH3:21]>>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH2:25][C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Reactant: CCOC(=O)CI
Product: CCOC(=O)CN1CCc2c(sc(N)c2C(=O)c2ccc(Cl)cc2)C1
Yield: 70 %

Procedure:
The same procedure as in Example 17 was used except an equivalent amount of 2-amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno[2,3-c]pyridine was used in place of 2-amino-3-benzoyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), and an equivalent amount of ethoxycarbonylmethyl iodide was used in place of methyl iodide (3 mmol). (m.p. 105-106° C.; 70% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].C(N(C(C)C)CC)(C)C>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]([NH:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[O:19])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.8 %

Procedure:
The procedure described in Example 1 (step 1.4.) is followed. Starting from 5 g (21.90 mmol) of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate, 4.63 g (23 mmol) of 4-nitrophenyl chloroformate, 5.66 g (43.80 mmol) of diisopropylethylamine and 0.134 g (1.09 mmol) of N,N-dimethylaminopyridine gives 8.6 g of product in the form of an oil which is used as it is in the following step.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[I-].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1C=O
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: COCCC=Cc1nc(Br)ccc1OC

Procedure:
1.5 mmol of 6-bromo-3-methoxypyridine-2-carbaldehyde and (3-methoxypropyl)triphenyl-phosphonium iodide [133622-76-1] are reacted in analogy to building block 24a. The title compound is identified by means of the Rf.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH:14]([CH2:26][CH2:27][CH2:28][CH:29]1[O:31][CH2:30]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:13])[CH3:12]>O>[C:11]([CH:14]([CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH2:30][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)=[O:22])(=[O:13])[CH3:12]
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C(CCCCCCC(=O)OCc1ccccc1)CCCC(O)COCc1ccccc1
Reaction time: 18 h

Procedure:
Sodium hydride (0.04 mole) is added in portions with stirring to benzyl alcohol (25 ml.). To the resulting solution, ethyl 8-acetyl-12,13-epoxytridecanoate (0.02 mole) is added and the mixture allowed to stand 18 hours at 55°-60°. The reaction mixture is then cooled and treated with water. The organic layer is separated and dried over magnesium sulfate. Excess benzyl alcohol is removed by distillation in vacuo by means of the rotary evaporator at oil pump pressure. The residue consists mainly of the title compound and is used in the next step without purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][CH:31]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12i and 3-bromoanisole
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:7])[N:6]=1.Br[CH2:16][C:17]([OH:19])=[O:18]>CN(C=O)C>[C:17]([CH2:16][S:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:7])[N:6]=1)([OH:19])=[O:18]
Reactant: CCOC(=O)CCc1sc(S)nc1C
Reactant: O=C(O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1sc(SCC(=O)O)nc1C
Reaction time: 2 h
Yield: 152.7 %

Procedure:
2 g (8.6 mmol) of ethyl 3-(2-mercapto-4-methyl-1,3-thiazol-5-yl)propionate were initially introduced into 40 ml of dry DMF, and 1.49 g (8.6 mmol) of bromoacetic acid were added. After 2 hours, the solvent was removed in vacuo, and 3.8 g of ethyl 3-[2-(carboxymethylthio)-4-methyl-1,3-thiazol-5-yl]propionate were obtained as an oil. The crude product was taken up in 25 ml of ethanol, 33 ml of 1N sodium hydroxide solution were added, and the reaction mixture was heated at 50° C. After the reaction was complete, the ethanol was removed in vacuo, and the aqueous residue was taken up in concentrated hydrochloric acid at pH 3.0, and the solution was extracted with ethyl acetate. 1.6 g (71%) of the title compound were obtained from the organic phase after drying with MgSO4, evaporation and crystallization with diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[NH:16][N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:25]([O:27][CH3:28])=[O:26].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[N:16]([C:25]([O:27][CH3:28])=[O:26])[N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)n1c(=O)c2c(n1C)NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1

Procedure:
The product from Example 1 (0.1 g) in methylene chloride (10 mL) was stirred overnight with methyl chloroformate (0.04 mL) and pyridine (0.06 mL). The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide 0.038 g of the title compound. 1H NMR (DMSO-d6) δ 2.32 (t, 2H), 2.72 (m, 2H), 3.65 (s, 3H), 3.7 (s, 3H), 4.72 (s, 1H), 7.11 (m, 1H), 7.22 (t, 1H), 7.32 (dd, 1H), 10.80 (s, 1H); MS (ESI+) m/z 438 (M+H)+; Anal. Calcd for C18H15N3BrFO4: C, 49.54; H, 3.44; N, 9.63. Found: C, 49.69; H, 3.27; N, 9.72.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[S:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][NH:9][CH2:8][CH2:7]1>ClCCl>[C:1]([N:9]1[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:6][CH2:7][CH2:8]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: c1ccc2c(c1)CNCCS2
Solvent: ClCCl
Product: CCC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of propionyl chloride (2.39 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (8.58 g, prepared as described in the first paragraph of Example 6 above) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 45 minutes, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethanol (98:2) as eluent gave 4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil. Yield 2.9 g.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[H][H]>CO.[C].[Pd]>[CH3:18][C@H:10]1[C@H:9]([NH:8][C:7]2[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=2)[CH2:14][C@@H:13]2[CH2:15][C@H:11]1[C:12]2([CH3:16])[CH3:17]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1)C2(C)C
Yield: 100 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (300 mg, 0.92 mmol) and 10% palladium-carbon (50 wt %, 30 mg) in methanol were stirred in a hydrogen stream at room temperature for 1 day. The reaction solution was filtered through celite, and the filtrate was concentrated to give the desired product (100% yield).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16].IC>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH3:1])[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2M solution of “butyllithium (4.18 mL, 8.4 mmol) at −78° C. under nitrogen. After 15 min at this temperature the solution was raised to and held at 0° C. for 15 min prior to re-cooling to −78° C. and treatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31 mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rt over 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10 mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15 mL), and dried over anhydrous magnesium sulfate. Concentration of the combined organic extracts afforded a yellow solid. NMR (CDCl3) consistent with crude, desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17].C(=O)([O-])[O-].[K+].[K+]>CCOCC.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C@@H:16]([C:15]([O:14][CH3:13])=[O:19])[CH3:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)[C@@H](C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyrimidine (17.5 g, 90 mmol) in ether (100 mL) at —OC was added a solution of D-alanine methyl ester hydrochloride (12 g, 85.96 mmol) in water (50 mL). To the resulting mixture was added potassium carbonate (71.2 g, 515.5 mmol) in portions with vigorous stirring. Then the reaction was allowed to warm up to rt and stirred for 16 h. The precipitated solid was filtered to afford desired product as yellow solid (4 g). Ether layer was separated from filtrate, the aqueous layer was extracted with ether (50 mL×3). Combined ether layers were dried (Na2SO4), evaporated to give a crude residue, which was then purified by silica gel flash chromatography to give another 2.7 g of desired product. 1HNMR (300 MHz, CDCl3): δ 1.61 (d, J=7.2 Hz, 3H), 3.82 (s, 3H), 4.90-5.0 (m, 1H), 8.75 (br s 1H) and 9.07 (s, 1H).
Reaction SMILES: [F:1][CH:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@:16]2([F:25])[C@H:4]([C@H:5]3[C@:13]([CH3:27])([CH2:14][C@@H:15]2[OH:26])[C@@:8]([OH:28])([C:9](=[O:12])[CH2:10][SH:11])[C@@H:7]([CH3:29])[CH2:6]3)[CH2:3]1.[CH:30]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31]>>[F:1][CH:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@:16]2([F:25])[C@H:4]([C@H:5]3[C@:13]([CH3:27])([CH2:14][C@H:15]2[OH:26])[C@@:8]([OH:28])([C:9](=[O:12])[CH2:10][S:11][C:38](=[O:39])[CH:33]([NH:32][CH:30]=[O:31])[CH2:34][CH2:35][S:36][CH3:37])[C@H:7]([CH3:29])[CH2:6]3)[CH2:3]1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CC(F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3CC(F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@H](O)C[C@@]21C
Yield: 32.8 %

Procedure:
The title compound (0.027 gm) was prepared from 6,9-difluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.06 gm) and (N-formyl-L-methionine (0.175 gm) in the same manner as in Synthetic Example 1.