Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:32])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][CH:24]([N:27](C)[C:28](=O)C)[CH2:23]4)=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][CH:24]([NH:27][CH3:28])[CH2:23]4)=[CH:18][CH:17]=3)=[O:32])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N(C)C1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)nc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Product: CNC1CCN(c2ccc(NC(=O)Nc3ccc(OC4CCCC4)nc3)cc2)C1

Procedure:
N-(1-{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N -methylacetamide was treated with sodium hydroxide solution by method D. This resulted in the product with the molecular weight of 395.51 (C22H29N5O2); MS (ESI): 395 (M+H+).
Reaction SMILES: C(O)[C@H]1O[C@H](NC2[O:13][C@@H:12]3[C@@H:14]([OH:21])[C@H:15]([OH:20])[C@:16]([OH:19])([CH2:17][OH:18])[C@@H:11]3[N:10]=2)[C@H](O)[C@@H](O)[C@@H]1O.O>Cl>[NH2:10][CH:11]1[C:16]([CH2:17][OH:18])([OH:19])[CH:15]([OH:20])[CH:14]([OH:21])[CH:12]1[OH:13]
Reactant: OC[C@H]1O[C@H](NC2=N[C@@H]3[C@H](O2)[C@@H](O)[C@H](O)[C@]3(O)CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: NC1C(O)C(O)C(O)C1(O)CO
Temperature: 100 °C
Yield: 54 %

Procedure:
A solution of 19.3 mg of trehazolin (prepared as described in Example 1 above) dissolved in 1 ml of 4N aqueous hydrochloric acid was placed in an ampoule and hydrolyzed by heating it at 100° C. for 24 hours. At the end of this time, the reaction mixture was mixed with water and then concentrated to dryness by evaporation under reduced pressure. The residue was again mixed with water and concentrated to dryness by evaporation under reduced pressure, to distill off the hydrochloric acid. The residue from this distillation was dissolved in 20 ml of water, and the pH of the solution was adjusted to a value of 6.0. The resulting solution was passed through a column of 20 ml of Amberlite CG-50 (NH4+)--trade mark--and the column was washed with 60 ml of deionized water and then eluted with 0.2N aqueous ammonia. The eluate was concentrated by evaporation under reduced pressure, and the residue was lyophilized to give 5.1 mg of impure 5-amino-1 -(hydroxymethyl)cyclopentane-1,2,3,4-tetraol as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=1>C(O)(CC)(C)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:57][C:53]1[N:52]=[C:51]([NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:56]=[CH:55][CH:54]=1
Reactant: Cc1cccc(Br)n1
Reactant: NC(=O)c1ccsc1N
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Product: Cc1cccc(Nc2sccc2C(N)=O)n1

Procedure:
A suspension of 2-aminothiophene-3-carboxamide (6.26 g, 44.0 mmol), potassium carbonate (6.08 g, 44.0 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (0.667 g, 1.40 mmol), dibenyzlideneacetone bis(triphenylphosphine) (0.293 g, 0.32 mmol), and 2-bromo-6-methylpyridine (4.55 mL, 40 mmol) in tert-amyl alcohol (80 mL) in a 250 mL round bottom flask with attached reflux condenser was placed under an argon atmosphere by performing six vacuum/argon flush cycles. The reaction was heated to reflux for 18 hours. The flask was charged with more 2-dicylohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (0.330 g, 0.7 mmol) and dibenyzlideneacetone bis(triphenylphosphine) (0.146 g, 0.160 mmol) and refluxed for an additional 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate, and this suspension was filtered. The layers of the filtrate were separated and the organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The resulting solid was triturated with a 1:1 mixture of ethyl acetate and hexanes to afford the title compound as a grey solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[N:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:5])[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH:15]=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[N:8][C:7]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
A mixture of 0.080 g (0.2 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1b), 2 mL of dichloromethane and 0.027 mL (0.24 mmole) of 1-methyl-piperizine was stirred at ambient temperature for 10 minutes, then 0.064 g (0.3 mmole) of sodium triacetoxyborohydride was added. The mixture was stirred at ambient temperature for 2 hours and was then diluted with 10 mL of dichloromethane. The mixture was washed with 3 mL of saturated sodium bicarbonate. The aqueous layer was extracted twice with 5 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-5:95) to give 0.066 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1c) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)C(=O)c2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(CCBr)cc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(=O)c2ccccc2)cn1

Procedure:
In analogy to the procedure described for the synthesis example 43 (step 2), the title compound N-(6-methyl-pyridin-3-yl)-2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide (MS m/e: 413.2 [M+H]+) was prepared from N-(6-methyl-pyridin-3-yl)-2-oxo-2-phenyl-acetamide and 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:17]>CN(C)C=O.O>[NH2:1][C:2]1[N:3]([CH3:17])[C:4](=[O:13])[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: CI
Reactant: Cn1cc(I)c2c(=O)[nH]c(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N)nc2c(c(I)cn2C)c1=O
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 2-amino-5-iodo-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (15.4 g, 53.1 mmol) in N,N-dimethylformamide (150 ml) was added sodium hydride (66% dispersion in oil, 1.93 g, 53.1 mmol) and iodomethane (3.31 ml, 53.1 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (×2) and ethyl acetate-tetrahydrofuran (×2). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 50-100% hexane/ethyl acetate gradient mixture, and the desired fractions were concentrated in vacuo. The residual crystals were washed with diethyl ether to give 12.3 g (76%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH:8][C:17]1[S:18][CH:19]=[CH:20][N:21]=1
Reactant: Brc1nccs1
Reactant: CCOC(=O)C(C)c1ccc(N)c(F)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(Nc2nccs2)c(F)c1
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A mixture of ethyl 2-(3-fluoro-4-aminophenyl)propionate (15 g) and 2-bromothiazole (11.7 g) is stirred at 150°-155° C for 15 minutes. The reaction mixture is dissolved in methylene chloride and the solution is washed with an aqueous solution of sodium hydrogen carbonate and dried. The solvent is evaporated. The residue is subjected to chromatography using alumina. From benzene eluate, ethyl 2-[3-fluoro-4-(N-thiazol-2-ylamino)phenyl]propionate (13.3 g) is obtained as oily substance boiling at 162°-164° C at 0.2 mmHg.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>CCOCC>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:9]=1[NH:10][C:11](=[O:20])[CH2:12][CH:13]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)CCCSc1ccccc1NC(=O)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCCSc1cccc2c1NC(=O)CC2c1ccccc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
2'-(3-Dimethylaminopropylthio)cinnamanilide, hydrochloride (30.0g) is mixed with polyphosphoric acid (700g) with stirring and heating. The temperature is allowed to reach 130°-145° C where the mixture is maintained for 15 minutes. After cooling to 60° C, the mixture is poured onto 2 liters of crushed ice and gradually treated with 1 kg. of potassium carbonate (foaming is partially controlled by addition of ethanol and ether). The basic solution is extracted with 200 ml of ether-100 ml of chloroform (3 times). The organic phases are combined, washed with 100 ml of water, dried over magnesium sulfate, filtered and the filtrate evaporated to give 24.2 g of a syrupy residue. Distillation of this material gives 17.7 g of distillate; boiling point 120°-220° C(0.1 mm of Hg). Subsequent fractionation gives 3.2 g of forerun, 2-(3-dimethylaminopropylthio)aniline, boiling point 120°-140° C(0.1 mm of Hg) and 14.0 g of pale yellow distillate; boiling point 170°-190° C(0.1 mm of Hg). This material partly solidifies and is crystallized from 5 ml of isopropanol to give 10.7 g of colorless solid, melting point 57°-80° C. After crystallization from 10 ml of acetonitrile, the material weighs 9.5 g, melting point 57°-90° C. The melting point indicates that this material is a mixture and an attempt is made to separate the mixture as a salt. A solution of 9.4 g of the base in 100 ml of chloroform is treated with 4.0 ml of 6.9 N ethanolic hydrogen chloride. The resulting yellow solution is diluted to 400 ml with ether to give a yellow amorphous product weighing 9.2 g, melting point 145°-147° C (sintering 130° C). Since this material is only partly soluble in water, a separation of this mixture is attempted by suspending 8.3 g of material in 150 ml of water. After 30 minutes, the solid is filtered, air-dried (wt. 2.3 g, melting point 104°-106° C), and the filtrate is made basic by the addition of a solution of 10 g of potassium carbonate in 20 ml of water. The liberated base is extracted with 100 ml of chloroform-200ml of ether (twice), the organic phases combined, dried over magnesium sulfate, filtered and the filtrate concentrated to give 5.0 g of the title compound, melting point 64°-66° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH2:10]([O:12][C:13]1[N:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][C:14]=1[C:15](OCC)=[O:16])[CH3:11].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]1[N:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH2:32]2)(=[O:26])=[O:25])=[CH:20][C:14]=1[CH:15]=[O:16])[CH3:11]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
DIBAL-H (14.8 mL) was added dropwise to a solution of ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinate (5.0 g, 13.5 mmol; prepared as described in WO 99/54333) in toluene (100 mL) at −78° C. under nitrogen. The mixture was held at −78° C. for 1 hour and then water (20 mL) was added dropwise. The mixture was allowed to warm to room temperature and then water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated and the aqueous phase re-extracted. The combined organics were washed with brine and concentrated under vacuum to give the product as a brown oil (1.64 g, 36%).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[CH:19])=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; dibenzyl-[1-(4-trimethylsilanylethynylphenyl)-cyclopropyl]-amine (Intermediate 128, 100.0 mg, 0.26 mmol) in methanol (5 mL) was treated with potassium carbonate (60.0 mg, 0.44 mmol) and stirred overnight at ambient temperature. The crude alkyne (80 mg, 99%) was used directly in the next reaction.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[CH2:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][NH:51]1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][N:51]1[C:29]([C:28]1[C:24]([CH3:23])=[N:25][O:26][C:27]=1[CH2:32][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:40])=[O:31]
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1Cc2ccccc2C1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1,5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and isoindoline (0.11 mL, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (EI) 347 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[C:13](OC)[CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].NC1C=[C:28]([O:30]C)C=CC=1C#N>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([O:30][CH3:28])[C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(C#N)c(N)c1
Reactant: CCOC(=O)c1ncc2[nH]c3cc(OC)ccc3c2n1
Product: CCOC(=O)c1ncc2[nH]c3cccc(OC)c3c2n1

Procedure:
The 7-methoxy-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester is produced analogously, but starting with 2-amino-4-methoxybenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23]C)=[O:22])=[C:17]([CH3:27])[CH:16]=2)[S:11][CH:12]=1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:17]([CH3:27])[CH:16]=2)[S:11][CH:12]=1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccccc3Br)cs2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCc2nc(-c3ccccc3Br)cs2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-((4-(2-bromophenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate (20 mg, 0.04 mmol) is dissolved in THF (1 mL). A solution of 1 M LiOH in H2O (0.2 mL) is added, and the mixture is stirred for 1 h at rt. The mixture is acidified with 1 M HCl (0.25 mL); EtOAc (10 mL) is added and the organic layer is washed with brine (5 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound A1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.74 (dd, J=1.6, 8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (dd, J=1.2, 8.0 Hz, 1H), 7.38 (dt, J=1.2, 7.6 Hz, 1H), 7.22 (dt, J=1.6, 7.6 Hz, 1H), 6.90 (d, J=2.8 Hz, 1H), 6.78 (dd, J=2.8, 8.8 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.37 (s, 2H), 4.63 (s, 2H), 2.28 (s, 3H). MS calcd. for C19H17BrNO4S (M+H+) 434.0. found 433.9.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([NH:25][NH2:26])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:18]([O:22][C:23]([NH:25][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-oxo-1-piperidinecarboxylate (10.0 g, 42.9 mmol), tert-butyl-1-hydrazinecarboxylate (5.70 g, 42.9 mmol) and sodium triacetoxyborohydride (13.6 g, 64.1 mmol) were stirred together for 4 hours at room temperature in dichloromethane/acetic acid (40 ml, 10% solution). The solvents were evaporated under reduced pressure. The residue was basified with saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a colourless gum, 14.2 g.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[CH:13][C:12]=1[O:20][CH3:21])=[O:10].[Br:22][CH2:23][C:24](Cl)=[O:25]>ClCCl.O>[CH3:21][O:20][C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:2]([CH3:1])[C:24](=[O:25])[CH2:23][Br:22])=[O:10]
Reactant: O=C(Cl)CBr
Reactant: CNc1ccccc1C(=O)c1c(OC)cc(C)cc1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1C(=O)c1ccccc1N(C)C(=O)CBr
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a mixture of 10 g of (2,6-dimethoxy-4-methylphenyl) (2-methylaminophenyl) ketone in 100 ml of dichloromethane and 20 ml of water, cooled to -10° C., are added dropwise 6.34 g of bromoacetyl chloride in 20 dichloromethane. The reaction mixture is allowed to return to room temperature and is then stirred vigorously for 2 hours. The phases are separated after settling has taken place and the organic phase is successively washed with water, dried over sodium sulphate and evaporated to dryness to give beige crystals melting at 121° C.; Yield=99%.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]1=O)=[O:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[NH:20]>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([C:19]2[N:20]=[C:3]([OH:4])[C:5]3[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[N:21]=2)[CH:22]=1
Reactant: COC(=O)C1CC(C)(C)CC1=O
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CCO
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(O)c2C1
Yield: 58.8 %

Procedure:
A solution of 4,4-Dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (2.08 g, 12.21 mmol) and 5-Chloro-2-fluoro-benzamidine (2.32 g, 13.44 mmol) in 100% ethanol (40 mL) was heated to reflux overnight, then cooled and evaporated. The residue was dissolved in 1N (aq.) NaOH (50 mL) and washed with methylene chloride (2×50 mL). The aqueous layer was then acidified with glacial acetic acid to pH 4 and extracted with methylene chloride (2×100 mL). The organic extracts were dried (brine and MgSO4) and evaporated to give crude product, which was purified by chromatography (CH2Cl2, 0-10% MeOH) to give the desired product as a cream solid (2.10 g, 59% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[S:7][C:8](/[CH:19]=[C:20](\[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)/[C:21]([O:23]CC)=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[S:7][C:8](/[CH:19]=[C:20](\[C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)/[C:21]([OH:23])=[O:22])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]=2[CH:4]=1
Reactant: CCOC(=O)/C(=C/c1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Oc2c(/C=C(/C(=O)O)c3ccncc3)sc3cc(OC)c(OC)cc23)cc1

Procedure:
A solution containing 3 mmol of the product of Example 1, 6 ml of an aqueous 1N sodium hydroxide solution and 20 ml of ethanol is refluxed for 2 hours. After returning to room temperature, the reaction mixture is concentrated under reduced pressure and the residue is then diluted in water and subsequently taken up in diethyl ether. The organic phase is then rendered acidic by the addition of 6 ml of a 1N HCl solution. A precipitate forms, which is filtered, rinsed with water and then dried under reduced pressure, enabling 1.3 g of the expected compound to be obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[N:19]1[CH2:25][CH2:26][NH2:27]>>[CH3:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[N:19]1[CH2:25][CH2:26][NH:27][C:14]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by a similar method to Preparation 4 from (2S)-1-(tert butoxycarbonyl)-2-piperidinecarboxylic acid [see Preparation 13] and 2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamine [J. Med. Chem., 27; 5, (1984), 684-691]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 92:8, by volume, dichloromethane:methanol/0.88 aqueous ammonia solution (20/1), in 1% increments to afford tert-butyl (2S)-2-[(2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamino)carbonyl]-1-piperidinecarboxylate as an oil.