Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.Br[CH2:37][CH:38]1[O:42][CH2:41][CH2:40][O:39]1>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:37][CH:38]2[O:42][CH2:41][CH2:40][O:39]2)[C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: BrCC1OCCO1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC3OCCO3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
NaH (1.5 eq, 60% dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available methyl indole-6-carboxylate) in DMF (0.1 M) and once effervescence had subsided the solution was stirred at RT for a further 30 min. 2-bromomethyl-1,3-dioxolane (4 eq) and catalytic (0.025 eq) KI were then added and the mixture heated at 50° C. for 36 h. The reaction mixture was then allowed to cool to RT, quenched with aqueous HCl (1 N) and extracted with EtOAc. The organics were washed with aqueous HCl (1 N) (3×), water and brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. Purification was by flash chromatography (10% EtOAc/PE) to give a pale yellow solid that was triturated with Et2O/PE) to afford the title compound as a white solid (69%); MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[N:15]([N:27]=[C:28]([C:30](OCC)=[O:31])[CH:29]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:18]=2)[S:5][C:6]=1[C:7]#[N:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.Cl>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[N:15]([N:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:18]=2)[S:5][C:6]=1[C:7]#[N:8]
Reactant: CCOC(=O)c1cc2c(NCCNc3nc(N)c(C#N)s3)nc(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1sc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cn3nc(CO)cc23)nc1N
Reaction time: 2 h

Procedure:
100 mg (0.184 mmol) of ethyl 4-({2-[(4-amino-5-cyano-1,3-thiazol-2-yl)amino]ethyl}amino)-6-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate (Example 11) were dissolved in 10 ml of THF, and 0.276 ml (0.276 mmol) of a solution of lithium aluminum hydride (1 mol/l) in THF was added dropwise at RT. The mixture was stirred for 2 h, and after complete conversion first methanol was added, and then the pH was adjusted to pH=5 using dilute hydrochloric acid. The mixture was extracted repeatedly with ethyl acetate. Removal of the solvent and purification by preparative HPLC gave 61 mg (64% of theory) of the product as a solid.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[CH3:3][CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(C)Br
Reactant: c1cncc(NC2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(C)N1CCC(Nc2cccnc2)CC1

Procedure:
A mixture of 52 parts of 2-bromopropane, 19 parts of N-(4-piperidinyl)-3-pyridinamine, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The residue is purified by column-chromatography over silica gel using methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 1.5 parts of N-[1-(1-methylethyl)-4-piperidinyl]-3-pyridinamine; mp. 100.7° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2ccccc2n1CCCCCl
Temperature: 60 °C
Yield: 61.5 %

Procedure:
2-methyl-1H-benzimidazole (13.2 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 13.7 g of 1-(4-chlorobutyl)-2-methyl-1H-benzimidazole, with a yield of 61.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([S:11]([CH2:14]C(O)=O)(=[O:13])=[O:12])[CH:5]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(S(=O)(=O)CC(=O)O)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
4-Chloro-3-[(carboxymethyl)sulfonyl]benzoic acid methyl ester (5.6 g) was mixed with pyridine (10 mL) and the mixture was refluxed for 30 min and then cooled to room temperature. The product was precipitated by adding water (30 mL). The precipitate was filtered, washed with water and dried (yield 2.5 g). 1H-NMR (400 MHz, DMSO-d6) d=3.43 (s, 3H), 3.92 (s, 3H), 7.92 (d, J=8.2 Hz, 1H), 8.24 (dd, J=8.2 Hz, 2.2 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](=O)([O:15]C)[O:13][CH3:14]>[H-].[Na+].C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]([O:13][CH3:14])=[O:15])[CH2:5]2
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Yield: 48 %

Procedure:
It is furthermore known from J. Pharm. Sci. 67(1) 1978, 81, to prepare the chloro-substituted indanonecarboxylic acid ester 5-chloro-2-methoxycarbonyl-1-indanone starting from 3-chlorobenzaldehyde. Here, 3-chlorobenzaldehyde is initially reacted in pyridine with malonic acid to give 3-chlorocinnamic acid. Following hydrogenation of the ethylenic double bond and cyclization to the 5-chloro-1-indanone, the latter is then reacted with dimethyl carbonate in the presence of sodium hydride and benzene as solvent to give 5-chloro-2-methoxycarbonyl-1-indanone. This synthesis method has the disadvantage of the multistep mechanism which considerably increases the likelihood of the formation of various by-products, which is reflected in only a low yield of 48%. Additionally, the total reaction requires the repeated use of substances such as sodium hydride and benzene, which are expensive, problematic with respect to safety or hazardous to health.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9]2.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9]2)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)CCc1cc2cc(OCCCN)ccc2[nH]1
Solvent: CC#N
Product: COC(=O)CCc1cc2cc(OCCCNC(=O)NCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To the solution of methyl 3-[5-(aminopropoxy)indolyl]propanoate (140 mg, 0.5 mmol), as prepared in the preceding step, in acetonitrile (10 mL) was added benzyl isocynate (135 mg, 1.0 mmol), and the mixture was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography on silica gel (methylene chloride to 5% ethyl acetate in methylene chloride) to give the title compound as a white solid (85 mg, 42%). 1H-NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 7.20 (d, J=8.9 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 6.81 (dd, J=8.8, 2.5 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 4.66 (br s, 2H), 4.41 (t, J=6.8 Hz, 2H), 4.35 (d, J=5.7 Hz, 2H), 4.06 (t, J=5.8 Hz, 2H), 3.66 (s, 3H), 3.43 (q, J=6.2 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 1.99 (t, J=6.1, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12]>C(O)(=O)C.O=[Mn]=O>[CH:2]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12])=[O:1]
Reactant: Cc1c(CO)sc(C(=O)O)c1C
Agent: O=[Mn]=O
Solvent: CC(=O)O
Product: Cc1c(C=O)sc(C(=O)O)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
3,4-Dimethyl-thiophene-2,5-dicarboxylic acid monoethyl ester is prepared according to a literature procedure (H. Wynberg et al., J. Org. Chem. 29 (1964) 1919-1921); LC-MS: tR=0.70 min, [M+H]+=not detectable; 1H NMR (D6-DMSO): δ 1.26-1.33 (m, 3H), 2.42 (s, 6H), 4.22-4.33 (m, 2H), 12.91 (s br, 1H). b) To a solution of 3,4-dimethyl-thiophene-2,5-dicarboxylic acid monoethyl ester (6.70 g, 29.4 mmol) in THF (70 mL), a solution of diisobutylaluminium hydride (DIBAL, 90 mL, 1 M in THF) is added at −78° C. The mixture is stirred at −78° C. for 30 min, then at −10° C. for 1 h before another portion of DIBAL (30 mL) is added. Stirring is continued at −10° C. for 30 min. Four more portions of DIBAL (30 mL) are added each time after stirring of the mixture for 30 min at −10° C. The reaction mixture is carefully quenched with water, diluted with 2 N aq. NaOH solution and extracted with DCM. The organic extracts are disgarded. The aq. phase is acidified by adding 25% aq. HCl and then extracted twice with EA. The organic extracts are washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to give crude 5-hydroxymethyl-3,4-dimethyl-thiophene-2-carboxylic acid (3.00 g) as a brownish solid; LC-MS: tR=0.66 min, [M+H]+=not detectable. c) A mixture of 5-hydroxymethyl-3,4-dimethyl-thiophene-2-carboxylic acid (3.00 g, 8.06 mmol) and MnO2 (2.55 g, 29.3 mmol) in acetic acid (60 mL) is stirred at 80° C. for 3 h, then at 70° C. for 16 h. The mixture is filtered over Hyflo and the filtrate is concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 10% of methanol. The obtained brownish solid is further purified by suspending the material in acetonitrile and methanol. The solid material is removed by filtration and the filtrate is further purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, acetonitrile/water (0.5% HCOOH), 10% to 95% acetonitrile) to give the title compound (435 mg) as a yellow solid; 1H NMR (D6-DMSO): δ 2.43 (s br, 6H), 10.16 (s, 1H), 12.35 (s br, 1H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:11]>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2ncc(Br)cc2C)c1
Yield: 37 %

Procedure:
Obtained (1.30 g, yield 37%) following the procedure described in Intermediate 27, starting with 2,5-dibromo-3-methylpyridine (11.96 mmol, 3.0 g), 3-ethoxyphenylboronic acid (11.96 mmol, 1.98 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[OH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Oc2cccnc2)cc1F
Reaction time: 8 h
Yield: 81.9 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (48 mg, 0.11 mmol), 3-hydroxypyridine (97 mg) and potassium carbonate (421 mg) were added in 40 ml DMF. The reaction mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate (30 ml×2) and water (30 ml). A combined organic layer was washed with H2O (30 ml×4) and brine (40 ml), dried with MgSO4, and then concentrated in vacuo. The residue was purified with column chromatography (hexane/ethylacetate=1/4) to yield the title compound (46 mg, 82%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:28][CH:29]1[C:39](=[O:40])[N:31]2[C:32]([C:36]([OH:38])=[O:37])=[CH:33][CH2:34][S:35][C@H:30]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([NH:28][CH:29]2[C:39](=[O:40])[N:31]3[C:32]([C:36]([OH:38])=[O:37])=[CH:33][CH2:34][S:35][C@H:30]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 58.3 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid (syn isomer, 3.2 g.), N,N-dimethylformamide (0.852 g.) and phosphoryl chloride (1.79 g.) in ethyl acetate (34 ml.) and a solution of 7-amino-3-cephem-4-carboxylic acid (1.95 g.) and bis(trimethylsilyl)acetamide (9.9 g.) in ethyl acetate (19.5 ml.) were treated in a similar manner to that of Example 15-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.9 g.).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16]Br)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][O:26][C:22]=2[CH:21]=1.C(N(C(C)C)CC)(C)C.CO>O>[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[C:23]4[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=4[O:26][CH:25]=3)[CH2:28][CH2:29]2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(CCBr)s1
Reactant: Fc1ccc2c(C3CCNCC3)coc2c1
Agent: Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccc(F)cc2)c(CCN2CCC(c3coc4cc(F)ccc34)CC2)s1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 0.917 g of 2-amino-5-(2-bromoethyl)-4-(4-fluorophenyl)thiazole hydrobromide, 0.511 g of 4-(6-fluorobenzofuran-3-yl)piperidine hydrochloride, 1.5 ml of diisopropylethylamine and 3 ml of methanol was stirred with heating under reflux for 12 hours. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with chloroform. The extract solution was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure, after which ether was added to the residue and the crystals were collected by filtration. The crystals were recrystallized from ethanol to obtain 0.57 g of 2-amino-4-(4-fluorophenyl)-5-[2-[4-(6-fluorobenzofuran-3-yl)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:27]1[CH:28]=[CH:29][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:25][CH:26]=1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C=Nc1ccc(-c2cccs2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(-c2cccs2)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (17 mg, 0.11 mmol) and diisopropylethylamine (55 uL, 0.32 mmol) in MeOH (2 mL) was added 2-(4-isocyanatophenyl)thiophene (43 mg, 0.22 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (5 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 7.53 (d, 2H, J=8.0 Hz), 7.42 (d, 2H, J=8.0 Hz), 7.29 (s, 2H), 7.05 (s, 1H), 4.65-4.63 (m, 1H), 3.77-3.53 (m, 2H), 3.23 (s, 9H), 2.58-2.48 (m, 2H); MS ESI 362.1 [M+H]+, calcd for [C18H23N3O3S+H]+ 362.46.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14](Cl)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([NH:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: CCn1cc(C(=O)Cl)c(=O)c2ccc(Cl)nc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2ccc(Cl)nc21
Reaction time: 72 h

Procedure:
7-Chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbonyl chloride (22.3 g) in dry dioxan (350 ml) was added slowly to 5amino-1H-tetrazole (7.9 g) and triethylamine (15.1 ml) in dry dioxan (350 ml) and the mixture kept 3 days at room temperature. The solid was collected and dissolved in aqueous dimethylaminoethanol. The solution was filtered and acetic acid was added to the filtrate. The solid that separated was collected and had m.p. above 400°.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH2:11])[C@@H:4]2[O:3]1.[CH3:13][C:14]1([CH3:38])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26]3[N:27]=[C:28]([N:31]4[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]4)[S:29][CH:30]=3)[CH:17]=[CH:16][C:15]1=2>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][CH:34]3[CH2:35][CH2:36][N:31]([C:28]4[S:29][CH:30]=[C:26]([C:18]5[CH:17]=[CH:16][C:15]6[C:14]([CH3:38])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=6[CH:19]=5)[N:27]=4)[CH2:32][CH2:33]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Reactant: CC1(C)O[C@H]2[C@H](N)CCC[C@H]2O1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](NC3CCN(c4nc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)cs4)CC3)CCC[C@H]2O1

Procedure:
The preparation is carried out analogously in THF starting from 27 mg (0.16 mmol) of (3aS,4R,7aR)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-ylamine and 60 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one. The purification is carried out by means of flash chromatography on silica gel.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14](Cl)=[O:15]>C(OCC)(=O)C.O>[CH2:1]([NH:7][C:14](=[O:15])[C:13]1[CH:12]=[C:11]([Cl:10])[CH:19]=[C:18]([Cl:20])[CH:17]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: NCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccco1)c1cc(Cl)cc(Cl)c1
Yield: 85.4 %

Procedure:
To a vigorously stirred solution of furfurylamine (2.78 g) in ethyl acetate (40 ml) was added sodium hydroxide (1.15 g) in water (45 ml), followed immediately by the addition of a solution of 3,5-dichlorobenzoyl chloride (6.0 g) in ethyl acetate (20 ml). Following the mild exothermic reaction the ethyl acetate layer was removed, dried (MgSO4), and evaporated. Crystallisation of the residue from cyclohexane gave the product (6.6 g) as colourless needles.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)c(C)n2)C1=O
Yield: 72.7 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (202 mg) described in Preparation Example 248 and 1-acetylimidazolidin-2-one (77 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (164 mg) was obtained.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]2[C:21](=[CH:20][CH:19]=1)[NH:24][C:2]([CH3:15])=[C:3]2[S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: Cc1[nH]c2ccc(Cl)cc2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 4-chlorophenylhydrazine hydrochloride.