Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[O:2]=[C:3]([CH2:8]C)[CH2:4][C:5](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:22]1([C:25]([OH:27])=O)[CH2:24][CH2:23]1.Cl>CO.CN(C)C=O>[CH:22]1([C:25](=[O:27])[CH2:8][C:3](=[O:2])[CH2:4][CH3:5])[CH2:24][CH2:23]1
Reactant: CCC(=O)CC(=O)O
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg]
Solvent: CO
Solvent: CN(C)C=O
Product: CCC(=O)CC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A stirred suspension of magnesium turnings (1.83 g, 75.0 mmol) in methanol (85 ml) was heated under reflux for 90 minutes. The suspension was cooled to room temperature and a solution of 3-ketopentanoic acid (17.4 g, 150.0 mmol) in methanol (15 ml) was added. The white suspension dissolved to give a pale yellow solution. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a pale yellow solid which was dissolved in N,N-dimethylformamide (50 ml). In a separate flask carbonyldiimidazole (13.4 g, 83.0 mmol) was added portionwise to a stirred solution of cyclopropanecarboxylic acid (6.46 g, 75.0 mmol) in N,N-dimethylformamide (150 ml) at room temperature under nitrogen. The reaction was stirred for 90 minutes and then the magnesium salt previously prepared was added dropwise. The reaction was stirred for 3 days and then poured into 1.0M hydrochloric acid (150 ml). The aqueous phase was extracted with ether (3×200 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (90:10, by volume) to provide the title compound (9.33 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:21])=[O:22]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: Cc1cccc(Cl)c1S(=O)(=O)Nc1cccc2cccnc12
Yield: 47.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, using 8-aminoquinoline (100 mg, 0.69 mmol), 2-chloro-6-methylbenzenesulfonyl chloride (230 mg, 1.04 mmol) and DMAP (cat.) gave the title compound (110 mg, 48%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]1(/[CH:12]=[C:7]2/[CH:6]([N:5]3[CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10][CH2:9][CH2:8]/2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCN[C@@H]1CCCC[C@@H]1C(O)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C(=C1\CCCCC1N1CCC1)\c1ccccc1
Yield: 31.8 %

Procedure:
A mixture of 2.5 g (9.5 mmoles) of cis-N-(3-hydroxypropyl)-N-[2-[hydroxy(phenyl)methyl]cyclohexyl]amine, 10 ml of toluene and 6.45 g of 48% v/v aqueous hydrogen bromide solution was stirred and heated on a steam bath for 3.5 hr. The resulting solution was cooled, basified with 20% sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, and saturated sodium chloride solution and then dried over magnesium sulfate and evaporated. The residue, 2 g, was chromatographed by high pressure liquid chromatography (HPLC) procedures using a Merck silica gel, size C column and 10% v/v methanol/in chloroform/1% v/v ammonium hydroxide mixture as eluting liquid, collecting 20 ml fractions. Fractions 1 to 14 gave no product material. Fractions 15 to 25 gave 0.686 g (30% yield) of (±)-(E)-1-[2-(phenylmethylene)cyclohexyl]azetidine, which was identified by NMR analysis comparison with the NMR of standard, authentic compound. Fractions 26 to 31 gave 0.25 g of a mixture, and fractions 32 to 50 gave 0.286 g of N-(3-hydroxypropyl)-N-[2-(phenylmethylene)cyclohexyl]amine which was identified by NMR comparison with a known standard sample, and also by conversion to its hydrochloride salt which was identical to a standard sample by NMR, UV and IR spectral analysis comparisons.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].[C:23](=O)=O.CC(C)=O.C[Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH3:23]
Reactant: O=C=O
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(C)cc(C(C)O)c2OC1C(F)(F)F
Reaction time: 2 h
Yield: 54 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605a, Step 1 (1.00 g, 3.18 mmole) was dissolved in anhydrous THF (10 mL) and the solution was cooled to −78° C. (dry ice/acetone). Methylmagnesium bromide (1.16 mL, 3.50 mmole) was added dropwise to the above solution, which was allowed to stir for 2 hours. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography (silica gel) with 10% MeOH/ CH2Cl2 to give a light yellow oil (0.3g, 54%): GCMS m/z 330.0 (M+). 1H NMR (CDCl3/400 MHz) 7.67 (s, 1H), 7.26 (s, 1H), 6.94 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 5.11 (m, 1H), 4.30 (m, 2H), 2.28 (s, 3H), 1.47 (m, 3H), 1.34 (m, 3H).
Reaction SMILES: [O-]CC.[Na+].[Na].[F:6][C:7]([F:12])([F:11])[C:8]([NH2:10])=[NH:9].Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](OCC)=[O:28])[C:23](=O)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]2[C:27]([OH:28])=[N:10][C:8]([C:7]([F:12])([F:11])[F:6])=[N:9][C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N=C(N)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium ethoxide, prepared from 3.2 g (133 mmol) of sodium metal and 200 mL of absolute ethanol, at ambient temperature was added 8.3 g (74 mmol) of trifluoroacetamidine followed by 17.8 g (60 mmol) of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride in portions over 15 min. The reaction mixture was stirred at ambient temperature for 1 h, then heated at reflux for 30 h. The mixture was concentrated in vacuo. The resultant red foam was partitioned between 300 mL of 1N aqueous sodium hydroxide solution and 300 mL of ether. The aqueous layer was washed with 300 mL of diethyl ether and the combined ether phases were extracted with 50 mL of 1N aqueous sodium hydroxide solution. The combined aqueous phases were cooled in an ice-water bath and neutralized to pH 7 with concentration hydrochloric acid. The solids were collected, washed with water, and dried in vacuo to give the title compound as a beige solid, which was used as is in Step B below. An analytical sample was prepared by recrystallization from isopropanol to give the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)[S:5][C:6]=1[Br:7].O.[NH2:16]N>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][NH:11][N:16]=2)[S:5][C:6]=1[Br:7]
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cc(Br)c(Br)s1
Solvent: CCO
Solvent: O
Product: Brc1cc(-c2cc[nH]n2)sc1Br
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of 1-(4,5-dibromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (9.6 mmol) and hydrazine hydrate (14.3 mmol) in 22 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 2.94 g (100% yield) 3-(4,5-dibromo-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[S:23])[CH3:20]
Reactant: NC1CCCc2sccc21
Reactant: CCN=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=S)NC1CCCc2sccc21
Temperature: 50 °C
Reaction time: 0.38 h

Procedure:
A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 100 ml. of dry tetrahydrofuran, and 6.06 grams of triethylamine is added. After stirring for 15 to 30 minutes, 5.23 grams of ethyl isothiocyanate in 20 ml. of dry tetrahydrofuran is added dropwise, and the mixture is heated for 2 hours at 50° C. The mixture is cooled and filtered, and the filter cake is washed with hexane. The filtrate is evaporated to dryness and poured on ice. The oil is extracted with ether, and the extract is washed with 1N sulfuric acid, water, and saturated sodium bicarbonate solution. The ether extract is dried and evaporated to dryness to afford an oil. This oil crystallizes in ether to afford 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea, melting point 106° C. to 112° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[NH3:12]>C(O)(C)C>[Cl:1][C:2]1[NH:3][C:4]([NH2:12])=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2
Reactant: N
Reactant: Clc1nc2ncnc-2c(Cl)[nH]1
Solvent: CC(C)O
Product: Nc1[nH]c(Cl)nc2ncnc1-2
Temperature: 120 °C

Procedure:
A mixture of 2,6-dichloro-1H-purine (5 g) and ammonia solution (79.2 mL, 2M in (isopropanol) was stirred and heated at 120° C. in an autoclave overnight. The reaction was cooled and concentrated in vacuo to give the title compound as an off-white solid in quantitative yield.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][NH:2]2.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].CCOCC>C(COC)OC>[CH2:12]([N:2]1[CH2:3][CH2:4][CH:5]2[CH2:9][CH:1]1[CH2:8][CH2:7][CH2:6]2)[CH:11]=[CH2:10]
Reactant: C1CC2CCNC(C1)C2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: C=CCN1CCC2CCCC1C2
Yield: 50.7 %

Procedure:
To a solution (6.5 ml) of 2-azabicyclo[3.3.1]nonane (100 mg, 0.62 mmol) in dimethoxyethane were added allylbromide (105 mg, 0.87 mmol) and potassium carbonate (94 mg, 0.68 mmol) and the mixture was heated at reflux temperature for 3.5 hours. Ether (10 ml) was added to the reaction mixture, followed by filtration and removal of the solvent, and the residue was purified with silica gel column chromatography (chloroform-methanol-triethylamine=100:9:1), to obtain 2-allyl-2-azabicyclo[3.3.1]nonane (52 mg, 51%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH:20]CCO)=[O:19])=[N:14][C:13]=2[CH3:24])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].N>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH2:20])=[O:19])=[N:14][C:13]=2[CH3:24])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1nc(NC(=O)NCCO)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Agent: N
Product: Cc1nc(NC(N)=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
The title compound is prepared by the same procedure as 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea (Example 88) by replacing 2-aminoethanol (part 88b) in this example with ammonia.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[C:5]([F:12])[CH:4]=1.C(=O)([O-])O.[K+].O.Br[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[NH:9][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:8]=2)=[C:5]([F:12])[CH:4]=1
Reactant: N=C(N)c1ccc(Br)cc1F
Reactant: CC(C)n1ncnc1C(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a rapidly stirred mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (9.84 g, 38.8 mmol), potassium hydrogen carbonate (15.6 g, 154.8 mmol), THF (98 mL) and water (16 mL) at reflux was added a solution of 2-bromo-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.0 g, 38.8 mmol) in THF (19 mL) over 15 min. The resulting mixture was stirred for 18 h at reflux before concentrating in vacuo. The resultant residue was treated with water and the solid formed collected by filtration, washed (water, then 1:1 diethyl ether: cyclohexane then diethyl ether) to give 5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole as a brown solid (10.1 g, 74%). 1H NMR δ (ppm) (CDCl3): 8.21-8.14 (1H, m), 7.90 (1H, s), 7.80 (1H, s), 7.47-7.38 (2H, m), 7.26 (1H, s), 5.91 (1H, br, s), 1.59 (6H, d, J=6.63 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:24]=1)=[O:4].[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:24]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc([N+](=O)[O-])cc3)ccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)Nc1cn2cc(Sc3ccc(N)cc3)ccc2n1

Procedure:
A suspension of 0.130 gms. of 2-(methoxycarbonylamino) 6-(p-nitrophenylthio) imidazo [1,2-a] pyridine in 30 ml. of glacial acetic acid is reduced at 40 psi. of hydrogen with 0.130 gm. of 5% palladium on carbon. When the uptake of hydrogen is complete, the catalyst is removed by filtration and the filtrate is evaporated to dryness in vacuo. The residue is stirred with saturated aqueous sodium bicarbonate and the resultant solids are collected by filtration, washed with water and dried in vacuo. The product melts 120°-175° C. Mass spectral data confirms the molecular ion of the product.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].Cl>C1COCC1.O.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:13])[CH2:1][CH3:2])=[CH:15][CH:16]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC[Mg]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 0.5M ZnCl2 in THF (60 mL, 30 mmol) in THF (20 mL) was treated with 2M ethyl magnesium chloride in THF (15 mL, 30 mmol) dropwise by syringe, cooled with an ice bath for about 10 minutes, stirred at room temperature for about 20 minutes, cooled to 0° C., and treated sequentially with Pd(PPh3)4 (1.73 g, 1.5 mmol) and a solution of 4-nitrobenzoyl chloride (6.12 g, 33 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 40 minutes, diluted with water, adjusted to pH 1 with 2N HCl and extracted three times with ethyl acetate. The combined extracts were washed sequentially with saturated Na2CO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide 2.17 g (40%) of the desired product as a yellow solid. Rf=0.6 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C@@H:4]2[CH2:3]1.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][C@@H:4]2[CH2:3]1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: O[C@@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Temperature: 100 °C
Yield: 9.3 %

Procedure:
A mixture of 3.81 g (26.8 mmol) of (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6, Step A), 19.8 g (134 mmol) of 2,5-dichloropyridine, 7.10 g (67.0 mmol) of sodium carbonate and 275 mL of isoamyl alcohol was heated at reflux for 72 hours. The mixture was cooled to about 100° C., filtered hot, and the filtrate concentrated in vacuo. Purification of the residue by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.63 g (9%) of the title compound of sufficient purity for use in subsequent reactions. m/z (MH+) 254.
Reaction SMILES: O[CH:2]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:27](=[O:32])C(C)(C)C)[CH:3]([CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)C(OC)=O.O.Cl>CO>[NH:11]1[CH2:10][CH2:9][CH:8]([C:3]2[C:27](=[O:32])[NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[CH:2]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1sccc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccsc2cc1C1CCNCC1
Yield: 97 %

Procedure:
Tert-butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(3-pivalamidothiophen-2-yl)propan-2-yl)piperidine-1-carboxylate (10 g, 21.34 mmol) was dissolved in MeOH (20 mL), water (20.00 ml), hydrochloric acid (concentrated, 20 ml, 244 mmol), the resulting red pink solution was heated, the color changed to dark tan, and the mixture was refluxed in a oil bath under N2 over night, conversion was completed as determined by LC/MS. Most of the solvent was removed on rotary vacuo, the resulting gum type residue was triturate with EtOAc/MeOH (10 mL/2 mL), filtered and washed with EtOAC/MeOH (10 mL/1 mL) to afford the expected product, 6-(piperidin-4-yl)thieno[3,2-b]pyridin-5(4H)-one (4.85 g, 97%), as a brown solid. 1H-NMR (400 MHz, MeOD) δ ppm 1.83-1.94 (m, J=13.41, 13.13, 13.13, 3.90 Hz, 2 H) 2.13 (d, J=13.85 Hz, 2 H) 3.08-3.19 (m, 4 H) 3.50 (dd, J=10.58, 2.01 Hz, 2 H) 7.08 (d, J=6.04 Hz, 1 H) 7.78 (d, J=5.54 Hz, 1 H) 7.96 (s, 1 H); Mass spec. 235.16 (MH+), Calc. for C12H14N2OS 234.08.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:27])[CH2:24][CH2:25][OH:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2]>O=[Pt]=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:27])[CH2:24][CH2:25][OH:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCN(C)CCO)ccc32)cc1
Agent: O=[Pt]=O
Product: CCc1ccc(-n2ccc3cc(CCCCCN(C)CCO)ccc32)cc1

Procedure:
In analogy to example 10.8 (PtO2 was used instead of Pd/C), 2-({5-[1-(4-Ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol was converted to yield 2-({5-[1-(4-Ethyl-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amino)-ethanol as colorless oil, MS: 365 (MH+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:11]([CH:12]([OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10]1>O1CCOCC1>[CH2:1]([NH:8][CH2:10][CH:11]([OH:9])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCC(O)C1CO1
Solvent: C1COCCO1
Product: CCCCCCCCCCC(O)C(O)CNCc1ccccc1
Reaction time: 12 h
Yield: 71.8 %

Procedure:
A 500-ml flask equipped with a stirrer was charged with 107 g (1 mol) of benzylamine, to which a solution of 5.2 g (71 mmol) of 1,2-epoxy-3-tridecanol in 170 ml of dioxane was added dropwise over 2 hours. After completion of the dropping, a reaction was conducted further for 12 hours at 80° C. Dioxane and excess benzylamine were distilled off under reduced pressure. The resultant residue was recrystallized from hexane, thereby obtaining 16.4 g (yield: 72%) of the title compound (IIh-1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A at 30° C., using a Quest 210 apparatus. This procedure gave 2.05 g (34%) of an off-white solid: mp 154° C.; MS (Ionspray, [M+H]+) m/z 375; Anal. Calcd (found) for C14H15ClN2O4S2: C, 44.9 (45.0)%, H, 4.0 (3.7)%, N, 7.5 (7.1)%.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:11][C:10](=[O:12])[NH:9][CH2:8]2)[C:3]1=[O:13].[H-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:9]1[C:10](=[O:12])[CH2:11][C:4]2([C:3](=[O:13])[N:2]([CH3:1])[C:6](=[O:7])[CH2:5]2)[CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CN1C(=O)CC2(CNC(=O)C2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC2(CC(=O)N(Cc3ccccc3)C2)C1=O
Reaction time: 1 h

Procedure:
A solution of 1.82 g (10 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 20 ml N,N -dimethylformamide was added gradually under a nitrogen atmosphere to 0.050 g (10.4 mmol) of 50% oil suspension of sodium hydride which had been previously washed twice with toluene and covered with 10 ml N,N-dimethylformamide. After stirring one hour there was added 1.40 g (11 mmol) of benzyl chloride and stirring was continued overnight at room temperature. After concentrating to a small volume in vacuo, the residue was diluted with 40 ml water and extracted twice with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate, and evaporated to give a solid. Crystallization from toluene:hexane to affore 1.74 g of the title compound, mp 157°-158° C.
Reaction SMILES: COC([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[C:17]([CH3:28])([CH3:27])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=O.C(N1C2C(=CC=CC=2)C(CS(Cl)(=O)=O)=[CH:33][C:32]1(C)[CH3:46])C.C(N)CCCCCCC.C(Cl)(Cl)Cl>C(O)C>[CH2:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([CH2:14][S:11]([NH:8][CH2:7][CH2:6][CH2:5][CH2:10][CH2:9][CH2:33][CH2:32][CH3:46])(=[O:12])=[O:13])=[CH:16][C:17]1([CH3:28])[CH3:27])[CH3:26]
Reactant: CCN1c2ccccc2C(CS(=O)(=O)Cl)=CC1(C)C
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCCCCCCCN
Product: CCCCCCCCNS(=O)(=O)CC1=CC(C)(C)N(CC)c2ccccc21
Yield: 81 %

Procedure:
(1-Ethyl-2,2-dimethyl-1,2-dihydroquinol-4-yl)-N-octyl-methanesulfonamide (12) is prepared similarly to compound (10) using compound (9) with n-octylamine. The product is isolated by column chromatography on silica gel with a gradient running from chloroform to ethanol.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[OH:10][CH2:11][CH2:12][NH:13][NH2:14]>CCO>[NH2:6][C:5]1[N:13]([CH2:12][CH2:11][OH:10])[N:14]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: NNCCO
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCO)n1

Procedure:
A solution of 4,4-dimethyl-3-oxopentanenitrile (125 mg, 1.0 mmol) and 2-hydroxyethyl hydrazine (75 mg, 1.0 mmol) in EtOH was heated to 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, 0% to 10% MeOH containing 1% NH4OH/CH2Cl2) to afford the desired amino-pyrazole.