Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.Cl.[CH:5]1([C:8]2[CH:9]=[C:10]([C:30]([O:32]CC)=[O:31])[C:11](=[O:29])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH:24]([CH3:28])[NH:23][CH2:22]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([C:30]([OH:32])=[O:31])[C:11](=[O:29])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH:24]([CH3:28])[NH:23][CH2:22]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)CNC4C)ccn2c1=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2ccc3c(c2)CNC3C)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
7.6 ml ethanol, 2.5 ml of THF and 1.3 ml of 1N hydrochloric acid were added to 312.5 mg of ethyl 1-cyclopropyl-9-methyl-8-(1-methylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylate (XIV) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and water was added to the resulting residue and the resulting residue was washed with ethyl acetate, and thereafter, the resulting water layer was concentrated under reduced pressure. 10 ml of water, 5 ml of ethanol and 3 ml of 1N sodium hydroxide were added to the residue, which was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and thereafter, dissolved in 4 ml of water and neutralized with 1N hydrochloric acid. The precipitated crystal was separated by filtering to obtain 139.1 mg of 1-cyclopropyl-9-methyl-8-(1-methylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]([CH2:12][CH2:13][O:14][CH3:15])[CH2:8][CH2:9][O:10][CH3:11])=[O:6].[OH-].[Na+].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>O1CCOCC1>[CH3:15][O:14][CH2:13][CH2:12][N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCN(CCOC)C(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCN(CCOC)C(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-N,N-bis(2-methoxyethyl)benzamide (1.01 g) in 1,4-dioxane (10 ml) was added 1N sodium hydroxide solution (5.2 ml) and phenyl chloroformate (0.55 ml) successively in an ice-cooled bath. The bath was removed and the reaction mixture was stirred vigorously for 1 hour, during which time phenyl chloroformate (0.25 ml) was further added. The mixture was extracted with dichloromethane and the organic layer was washed with water twice and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give phenyl 3-[N,N-bis(2-methoxyethyl)carbamoyl]phenylcarbamate (1.30 g) as a colorless powder. mp: 116-118° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.Cl>[OH-].[Na+]>[SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: CCOC(=O)c1cnn2c(S)cc(C)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(S)n2ncc(C(=O)O)c2n1

Procedure:
Ethyl 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (J. Med. Chem. 1981, 24(5), 610-13) was heated in 1N aqueous sodium hydroxide solution until all has passed into solution. The reaction mixture was cooled and its pH was adjusted to 1 with aqueous hydrochloric acid. The resulting precipitate was filtered off, dried and recrystallized from dimethylformamide. There was obtained 7-mercapto-5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid as a yellow powder having a of melting point of 161°-162° (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3C(=O)C4=CC=CC=C4C3=O)[CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.O.NN>>[NH2:22][CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][N:14]([CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2ccncc2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCN(C(c2ccccc2)c2ccncc2)CC1

Procedure:
The title compound was prepared in a quantitative yield in a similar manner to that described in Preparation 15' by reacting 4-[α-(4-pyridyl)benzyl]-1-(2-phthalimidoethyl)piperazine (prepared as described in Preparation 50') and hydrazine hydrate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24])=[CH:6][CH:5]=2
Reactant: CSC(=N)c1cccs1
Reactant: Cc1cc2cc(N)ccc2n1CCC1CCCN1C
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2cc(NC(=N)c3cccs3)ccc2n1CCC1CCCN1C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of compound 31 (0.32 g, 1.243 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.7 g, 2.486 mmol) at room temperature and stirred for 4 h. The reaction was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 32 (0.45 g, 99%) as a foam. 1H NMR (DMSO-d6) δ 1.48-1.68 (m, 4H), 1.87-1.98 (m, 2H), 2.01-2.18 (m, 2H), 2.22 (s, 3H), 2.39 (s, 3H), 2.92-2.98 (m, 1H), 4.07 (t, 2H, J=7.8 Hz), 6.09 (s, 1H), 6.19 (brs, 2H), 6.62 (dd, 1H, J=1.5, 8.5 Hz), 6.87 (s, 1H), 7.08 (dd, 1H, J=3.6, 4.9 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=5.4 Hz), 7.70 (d, 1H, J=3.6 Hz); ESI-MS (m/z, %) 367 (MH+, 62), 184 (100), 126 (37); ESI-HRMS calculated for C21H27N4S (MH+), calculated: 367.1950, observed: 367.1965; HPLC purity: 96.2% by area.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.Br[CH2:12][C:13](=O)[CH3:14].C(#N)C.[OH-].[Na+]>O>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:12]=[C:13]([CH3:14])[N:1]=2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(=O)CBr
Reactant: CC(C)c1ccc(N)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cn2nc(C(C)C)ccc2n1

Procedure:
3-Amino-6-isopropylpyridazine (0.41 g, 2.99 mmol) and bromoacetone (0.53 g, 3.10 mmol) were mixed with acetonitrile (5.0 ml) and heated for 6 hours under reflux. After the reaction was completed, water (20.0 ml) was poured into the reaction solution and adjusted to pH 9 with 20% aqueous sodium hydroxide solution. The reaction solution was extracted twice with ethyl acetate, and the extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:1) to give the title compound as brown oil. The yield was 0.30 g (57.2%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:25][C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[Cl:22]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccccc1Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (100 mg, 0.317 mmol) and 2-chlorobenzaldehyde (36 ul, 0.317 mmol) similar to Example 6. The residue was purified with hexane:ethylacetate (5:1, 4:1) to yield a light yellow solid (13.5 mg, 9.7%). 1H NMR (CDCl3): 8.10 (d, J=15.6 Hz, 1H), 7.73 (dd, J=2.3, 7.1 Hz, 1H), 7.43 (d, J=9.3 Hz, 1H), 7.41 (d, J=15.9 Hz, 1H), 7.33 (t, J=2.1 Hz, 1H), 7.32 (s, 1H), 7.3 (d, J=3.0 Hz, 1H), 7.14 (dd, J=3.2 Hz, 9.2, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.45-4.34 (m, 4H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30]([NH:40][CH2:41][C:42](O)=[O:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[C:30]([NH:40][CH2:41][C:42]([NH:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: Nn1cccc1C(=O)c1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.7 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (2.32 g, 11.2 mmol) was added in one portion to a stirred solution of 1-amino-2-benzoylpyrrole (2.1 g, 11.2 mmol) and carbobenzyloxyglycine (2.36 g, 11.2 mmol) in 70 ml of dichloromethane. The reaction mixture was stirred rapidly for 2.5 hours at room temperature and thereafter filtered to remove the precipitated dicyclohexylurea. Evaporation of the filtrate left 4.7 g of a semi-solid which was flash chromatographed (silica gel, 1:1 ethyl acetate-hexane) to give 3.75 g (88%) of powder, m.p. 96°-98°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:35])[CH:3]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:35])[CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 28.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (47 mg, 0.10 mmol) obtained in step 2 and ethanesulfonamide (52 mg, 0.5 mmol), the title compound (16 mg, 28%) was obtained.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:9]([C:11]3[O:15][C:14]([CH:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)=[N:13][C:12]=3[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCc1nc(C2CCCCC2)oc1C(=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: CCCc1nc(C2CCCCC2)oc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H30N4O3 (m/e) 398, obsd 399 (M+H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([C:10]1[N:15]=[C:14](O)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C>[C:6]([C:10]1[N:15]=[C:14]([Cl:3])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Temperature: 40 °C
Yield: 85 %

Procedure:
In cold (˜0° C.) POCl3 (20 mL) was dropped triethylamine (0.55 mL) with stirring. To this was added in parts ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 9.72 mmol). The mixture then warmed to 40° C. and stirred under Argon for 1 hour. The mixture was evaporated until free of POCl3, diluted with CHCl3 (100 mL) and poured carefully into ice (300 mL). The solution was stirred until it reached RT. The organic phase was separated, washed with sodium bicarbonate (100 mL), water (100 mL), dried (Na2SO4) and concentrated in vacuo to give ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (2.0 g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 4.34 (q, J=6.8 Hz, 2H), 1.33 (s, 9H), 1.27 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 243.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28](O)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1>ClCCl>[CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[O:17])([CH2:27][C:28]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)=[O:29])[C:7]1=[O:31])[CH3:2]
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(CO)cc2)c2ccccc21)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(CO)cc2)c2ccccc21)OCC
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
The carboxylic acid intermediate (234 mg) was dissolved in dichlormethane (10 mL), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (131 mg) and para-toluidine (73 mg) were added in that order. The mixture was stirred at 15-30° C. for 18 hours and concentrated. After diluting the residue with ethyl acetate and washing it with dilute hydrochloric acid and saturated bicarbonate water, it was dried on anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane/ethyl acetate=2/1) to obtain 204 mg of a white powder (90% ee, 80% yield from ester intermediate).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:18]([C:20]([CH3:22])=[O:21])[CH3:19].[Na]>C(O)C>[C:20]([C:22]#[C:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)(=[O:21])[CH2:18][CH3:19]
Reactant: CCC(C)=O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C#CC(=O)CC)cc1

Procedure:
Following the procedure in Example 1 using 7.1 parts of ethyl 2-(4-formylphenoxy)-2,2-dimethylacetate and 4.5 parts of methyl ethyl ketone in 10 parts by volume of ethanol containing 0.1 part of sodium metal provides ethyl 2-[4-(2-propionylethynyl)phenoxy]-2,2-dimethylacetate as an oil (1.5522). This compound has the following structural formula. ##SPC13##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[S:17][CH3:18])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(C)=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])=[C:11]([S:17][CH3:18])[CH:12]=1
Reactant: CSc1cc(O)ccc1C(=O)c1ccc(Br)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1cc(OCCCCCCBr)ccc1C(=O)c1ccc(Br)cc1

Procedure:
450 mg of (4-bromo-phenyl)-(4-hydroxy-2-methylsulphanyl-phenyl)-methanone are taken up in 7 ml of acetone and treated with 1.24 g of K2CO3 and 530 μl of 1,6-dibromohexane. The suspension is heated under reflux overnight, cooled, filtered and concentrated. After removing the excess 1,6-dibromohexane there are obtained 710 mg of [4-[6-(bromo)-hexyloxy]-2-methylsulphanyl-phenyl]-(4-bromo-phenyl)-methanone as a brown oil.
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: NCCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCCc2ccccc2)ccnc1Br
Yield: 65.4 %

Procedure:
Prepared according to the methods above using 2,4-dibromonicotinonitrile (100 mg, 0.382 mmol), 3-aminopropylbenzene (0.058 mL, 0.401 mmol) and Hunig's Base (0.080 mL, 0.458 mmol) in DMF (1.5 mL) to give the desired product as a white solid (79 mg). LC/MS (316/318, [M−H]−/[M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (dd, J=6.0, 0.5 Hz, 1H), 7.37-7.30 (m, 2H), 7.28-7.15 (m, 3H), 6.42 (d, J=6.0 Hz, 1H), 5.26 (br. s., 1H), 3.28 (td, J=7.0, 5.8 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.03 (quin, J=7.3 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)(C)C)c1O
Reaction time: 24 h
Yield: 57.8 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (30.0 g, 128 mmols), 2-thiohydantoin (14.8 g, 128 mmols), and sodium acetate (36 g) in acetic acid (200 ml) is stirred under nitrogen and heated to reflux. After 24 hours the mixture is allowed to cool, and is stirred into water (2 L). After an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-thioxo-4-imidazolidinone (24.6 g), mp 278°-279° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5](=[O:14])[CH:4]=1.[H][H]>C(OC(=O)C)(=O)C.[Pd]>[CH3:1][N:2]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:6](=[O:13])[CH3:7])=[C:5]([O:14][C:5](=[O:14])[CH3:4])[CH:4]=1
Reactant: CN(C1=CC(=O)C(=O)c2ccccc21)C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(N(C)C2CCCCC2)c2ccccc2c1OC(C)=O

Procedure:
A suspension of 3.5 g of 4-(N-methylcyclohexylamino)-1,2-naphthoquinone in 50 ml of acetic anhydride is hydrogenated at 45 lbs pressure and room temperature using 1.2 g of 10% palladium on carbon as catalyst. After uptake of hydrogen ceases and the red color of the solution is discharged (5 hours) the catalyst is removed by filtration. The acetic anhydride is evaporated under reduced pressure at 60° C. and the residue is taken up in toluene, treated with charcoal and filtered. The toluene solution is evaporated under reduced pressure and the product crystallized from 1:1 hexane-diethyl ether (100 ml) to afford 4-(N-methylcyclohexylamino)-1,2-diacetoxynaphthalene, the compound of formula II wherein NR1R2 represents N-methylcyclohexylamino, R3 represents hydrogen, and R4 and R5 represent acetyl, m.p. 103°-105° C.; hydrochloride salt, m.p. 165°-167° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([N:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[C@H:35]1[C:40](O)=[O:41])=O)(C)(C)C>CS(C)=O>[OH:39][C@H:36]1[CH2:37][CH2:38][NH:34][C@@H:35]1[C:40]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously starting from 150 mg (0.36 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 94 mg (0.40 mmol) of (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in DMSO. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off analogously using HCl in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([N:11]([CH3:12])[C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:1]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C(O)c1ccccc1)N(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Into a dry 1 L round-bottomed flask equipped with a magnetic stirrer was added (+)-pseudoephedrine (22.34 g, 135.22 mmol, 1.0 equiv), triethylamine (21.5 mL, 154 mmol, 1.14 equiv), and tetrahydrofuran (300 mL). The solution was cooled to 0° C. and hydrocinnamoyl chloride (25.08 g, 148.74 mmol, 1.1 equiv) in tetrahydrofuran (100 mL) was added via cannula over a 20 minute interval. After 30 minutes, the reaction was quenched with water. The amide was extracted from water (1 L) with ethyl acetate (400 mL, 120 mL, 120 mL), and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a white solid was obtained, which was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL) affording the hydrocinnamide as white crystals (30.24 g, 75% yield): mp 102°-104° C.; 1H NMR (300 MHz, C6D6) δ7.0-7.4 (m, 5H), 4.59 (br, 1H), 4.48 (t, 1H, J=7.1 Hz), 4.20 (m, 1H), 4.01 (dd, 1H, J=8.4 Hz, 2.4 Hz), 3.66 (m, 1H), 3.15 (m, 2H), 2.93 (t, 2H, J=7.7 Hz), 2.79 (s, 3H), 2.49 (m, 2H), 2.13 (m, 2H), 2.02 (s, 3H), 0.92 (d, 3H, J=7.0 Hz), 0.49 (d, 3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ174.3, 173.2, 142.2, 141.5, 141.3, 141.1, 128.6, 128.39, 128.36, 128.31, 128.29, 128.2, 127.6, 126.8, 126.4, 126.1, 125.9, 76.3, 75.3, 58.0, 36.1, 35.4, 32.3, 31.5, 31.1, 26.9, 15.2, 14.3; FTIR (neat film) cm-1 3374 (br, m), 3027 (m), 1621 (s), 1495 (m), 1454 (m), 1406 (m), 1118(m), 1048 (m), 753 (m), 701 (m); HRMS (FAB) Calcd for C19H24NO2 (MH+): 298.1808; Found: 298.1806.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:23][CH:21]([O:20][C:18](=[O:19])[O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:22]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.07 g (5.0 mmol) 4-benzyloxybenzyl alcohol and 0.786 g (5.5 mmol) 1-chloroethyl chloroformate in 25 ml CH2Cl2 is cooled to 0° C. and 0.435 g (5.5 mmol) pyridine added. After stirring at rt for 2 h the reaction mixture is quenched with 1N HCl, the organic phase separated and washed with sat. NaHCO3 solution and brine, dried over Na2SO4 and evaporated: 1.58 g (98%) (RS)-carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester as light yellow oil. 1H-NMR (CDCl3): 1.81 d, J=6 Hz, 3H; 5.07 s, 2H; 5.14 and 5.17, AB-system J=15 Hz, 2H; 6.43 q, J=6 Hz, 1H; 6.97 d, J=8.5 Hz, 2H and 7.30–7.45 m, 7H.