Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (80 mg, yield 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=[O:11])[CH:9]=[CH2:10]>>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:11])[CH2:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)O
Product: O=C1CC=Nc2ccccc21

Procedure:
The process of Scheme IX begins with the reaction of an aniline (structure 37) with an unsaturated acid, for example acrylic acid, followed by a cyclization reaction mediated by, for example, polyphosphoric acid to afford a 4-quinolinone. The nitrogen atom is then protected by treatment with a base, for example, 4-dimethylaminopyridine, followed by the addition of an acylating agent such as di-tert-butyldicarbonate, to afford a compound of structure 38. Addition of an organomagnesium or organolithium reagent, with, for example, ethyl magnesium bromide, affords an alcohol. Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 39. Nitration of a compound of structure 39 by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7-amino-1,2,3,4-tetrahydroquinoline of structure 40. A Knorr cyclization with a β-keto ester effected by, for example, zinc chloride, affords a compound of structure 41. A compound of structure 41 may be further transformed into a compound of structure 42 by acylation of the quinoline nitrogen, which may be accomplished in one of two ways. Treatment of structure 41 with an acid chloride, for example, acetyl chloride, followed by treatment with a base, for example, potassium carbonate, to afford a compound of structure 42. Alternatively, treatment of structure 41 may be treated with an anhydride, for example, trifluoroacetic anhyride, likewise to afford a compound of structure 42.
Reaction SMILES: [CH2:1]([C:5]([CH:7]1[CH2:12][CH2:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH2:8]1)=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:15]([OH:17])C.C=O.[OH-].[K+]>CO.C(O)(=O)C>[CH2:1]([C:5]([C:7]1([CH2:15][OH:17])[CH2:12][CH2:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH2:8]1)=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC1=C(C)CC(C(=O)CC(C)C)CC1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(C)CC(CO)(C(=O)CC(C)C)CC1

Procedure:
A mixture of 65.6 g (0.338 mole) of 3,4-dimethylcyclohex-3-enyl isobutyl ketone (Example XXII), 120 ml of ethanol and 109.6 g of 37% strength formaldehyde solution (=1.35 moles) is brought to a pH of 11-12 with a 15% strength solution of potassium hydroxide in methanol, and is then refluxed for 44 hours, the pH being checked. Thereafter the solution is brought to pH 5 with glacial acetic acid and the solvent is distilled off under reduced pressure. Water is added to the residue and after saturation with sodium chloride the mixture is extracted five times with toluene. The organic phases are dried over anhydrous sodium sulfate, the solvent is distilled off on a rotary evaporator and the residue is distilled under reduced pressure. 37.7 g of 3,4-dimethyl-1-hydroxy-methyl-cyclohex-3-enyl isobutyl ketone pass over at 112°-116° C./0.1 mm Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>[OH-].[Na+]>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2][CH2:3]1)([OH:9])=[O:8]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCC(C(=O)O)CC1

Procedure:
4-Carboxy-1-ethoxycarbonylpiperidine is prepared from piperidine-4-carboxylic acid (Aldrich, Steinheim, FRG), for example by reacting piperidine-4-carboxylic acid with ethyl chloroformate in aqueous sodium hydroxide solution for 2 h at from 0 to 5° C. The title compound is extracted from the aqueous phase by shaking with toluene. The toluene phase containing the dissolved title compound is dried over Na2SO4 and directly subjected to further use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:10]=1
Reactant: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1C=O
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a stirred solution of (4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)methanol (75 mg, 0.2 mmol) in CH2Cl2 (6 mL) was added Dess-Martin periodinane (102 mg, 0.24 mmol). The reaction was kept for 2 hrs and was diluted with EtOAc (10 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a white solid (75 mg). The crude product was purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give 4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde (65 mg, 91% for 2 steps) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].O=[C:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12.C([BH3-])#N.[Na+].[ClH:31]>C(#N)C.C(O)(=O)C>[ClH:31].[CH2:3]([N:2]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH3:1])[CH3:4]
Reactant: CCNC
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O

Procedure:
Compound No. 26 may also be prepared as follows: 8.5 ml of glacial acetic acid are added to the solution of 8.9 g of N-methyl-ethylamine in 100 ml of acetonitrile, followed by 7.5 g of 1-(2-oxo-propyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one and 1.7 g of sodium cyanoborohydride. The mixture is refluxed overnight, an additional1.7 g of sodium cyanoborohydride is added and refluxing is continued for an additional day. The mixture is cooled, acidified to pH=1 with hydrochloric acid and evaporated. Water is added to the residue, the mixture is washed with diethyl ether, filtered and the aqueous filtrate basified to pH=10-11 with 3 N aqueous sodium hydroxide. It is extracted with chloroform, the extract dried, evaporated and the residue is dissolved in the minimum amount of ethanol. The solution is combined with 2.15 ml of 8 N ethanolic hydrochloric acid, the precipitate collected and recrystallized from ethanol, to yield the 1-[2-(N-ethyl-N-methylamino)-propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, melting at 256°-257°.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11])=[O:22]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@@H]1O
Reaction time: 0.5 h

Procedure:
To a mixture of (1R,2S)-1-amino-2-indanol (500 mg, 3.35 mmol) and triethylamine (0.51 mL, 3.69 mmol) in anhydrous CH2Cl2 at 0° C. was added chloroacetyl chloride (0.295 mL, 3.69 mmol) dropwise. The resulting mixture was stirred for 30 min, quenched with saturated aqueous NaHCO3 (15 mL) and then extracted with EtOAc (2×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc 70:30 to 0:100, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][C:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NCC2(O)CCCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 18.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(18 mg, 0.050 mmol) described in example 92, 1-(aminomethyl)cyclohexanol hydrochloride (110 mg, 0.66 mmol) and triethylamine (0.28 mL, 1.98 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1-hydroxycyclohexyl)methyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (4 mg, 18% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.46 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.94 (m, 2 H), 4.12 (s, 2 H), 3.58 (s, 3 H), 3.48 (d, J=5.6 Hz, 2 H), 1.62-1.49 (m, 1 H); MS m/z 440 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[CH3:12][C:13]1[C:18]([CH3:19])=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N+:14]=1[O-:23]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:16]=[CH:15][N+:14]([O-:23])=[C:13]([CH3:12])[C:18]=2[CH3:19])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(Oc2ccc(Br)cc2F)cc[n+]([O-])c1C
Temperature: 180 °C
Yield: 45.9 %

Procedure:
To a room temperature solution of 4-bromo-2-fluorophenol (1 g, 5.23 mmol) in N-methylpyrrolidone (10 ml) was added sodium hydride (0.27 g, 6.79 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 2,3-dimethyl-4-nitro-pyridine 1-oxide (1.05 g, 6.28 mmol) was added The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was filtered through a diatomaceous earth pad and the filtrate was then diluted with EtOAc and washed with water. The solution was then extracted with additional EtOAc (2×150 ml). The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 23 (0.75 g, 46%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C1OCCOCCOCCOCCOC1.CS(O[CH:25]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=O)=O.C(Cl)Cl>CN(C=O)C>[N:1]([CH:25]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])=[N+:2]=[N-:3]
Reactant: COC(=O)c1ccccc1CCCC(Cc1ccccc1)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CCCC(Cc1ccccc1)N=[N+]=[N-]
Temperature: 85 °C

Procedure:
Sodium azide (1 g, 15.4 mmol) and 15-crown-5 (0.17 g, 0.77 mmol) were added to a stirred solution of 30e (2.9 g, 7.7 mmol) in DMF (60 mL). The mixture was heated at 85° C. for 24 h under argon atmosphere. Then DCM (300 mL) was added, the solution was washed with a saturated NaHCO3 solution (2×150 mL) and brine (3×200 mL), and dried over Na2SO4. After removal of the solvent under reduced pressure, the desired product was obtained as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:22])([F:21])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:5]>[Pt].CO>[ClH:1].[F:21][C:3]([F:2])([F:22])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:9]=1)=[O:5]
Reactant: O=C(NCc1ccc(F)c(-c2ccncc2)c1)C(F)(F)F
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: O=C(NCc1ccc(F)c(C2CCNCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A Parr flask is charged with compound 13 (123 g, 0.37 mol) and MeOH (740 mL) at rt, then 5% Pt/C (36.9 g, 30 w/w%) is added. The reaction flask is placed in a Parr hydrogenation system and charged with H2 at 50-60 psi. The mixture is shaken for >48 h while charging H2 until the pressure reached a steady state (H2 was refilled to 50-60 psi every 2-3 hours during day time while 10-20 psi is observed without any further refill after overnight). When HPLC analysis shows completion of the reaction, the reaction mixture is filtered through a pad of Celite. The filtrate is distilled at 40-50° C. while adding n-BuOAc (1.25 L). After completion of distillation of MeOH, additional n-BuOAc (1 L) is added. The resultant suspension is allowed to cool to rt overnight. The suspension is cooled to 10° C., filtered, and dried in oven at 50° C. to give 112 g (89%) of compound 14 as white solid: mp=134° C. Anal. Calcd for C14H10F4N2O—HCl: C, 50.24; H, 3.31; N, 8.37. Found: C, 50.16; H, 3.08; N, 8.38. MS (ESI) m/z 305.4 (M+H). 1H NMR (300 MHz, D2O) δ 7.16-6.98 (m, 3H), 4.34 (s, 2H), 3.42 (d, J=12.9 Hz, 2H), 3.14-2.99 (m, 3H), 1.98-1.81 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[NH2:4].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2.C(O)(=O)C>O>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][C:3]=1[N:4]1[C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=2[C:17]1=[O:22]
Reactant: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 69.7 %

Procedure:
2-Fluoro-4-chloro-5-cyclohexyloxyaniline (213 mg, 0.874 mmol), 3,4,5,6-tetrahydrophthalic anhydride (134 mg, 0.874 mmol) and acetic acid (10 ml) were charged into a 50 cc round-bottom flask, and heated for 15 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, water (50 ml) was added thereto, and extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the solvent was distilled off under reduced pressure to obtain a crude product (332 mg). The product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=19/1) to obtain N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (230 mg, 0.609 mmol, 70% yield). By recrystallization of the product from hexane/chloroform, it was isolated as white needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].[Na].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:6][C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)=[O:22])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
9.5 g of 2,6-dichlorobenzamide and 10.34 g of 3,4-dichlorophenylisocyanate in 25 ml of pyridine to which 1 g of sodium has been added are heated on a steam bath (100° C+) for 24 hours. The reaction mixture is poured on ice which contains concentrated hydrochlorid acid and the solid precipitate is thoroughly washed with successively water and alcohol. The substance is recristallized from acetonitrile. Melting point 232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[C:8]2[CH3:15].[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:12]([C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:14])=[CH:31][CH:32]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: COc1cccc2c(C)c(C(=O)O)[nH]c12
Reactant: CCOC(=O)N1CCC(Oc2ccc(N)cc2)C1
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3[nH]c4c(OC)cccc4c3C)cc2)C1

Procedure:
With a procedure similar to the example above, 3-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 7-methoxy-3-methyl-1H-indole-2-carboxylic acid and 3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C24H27N3O5 (m/e) 437, obsd 438 (M+H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[F:30][C:31]1[CH:36]=[C:35](F)[CH:34]=[CH:33][C:32]=1[CH2:38][C:39](=[O:41])[CH3:40]>>[F:30][C:31]1[CH:36]=[C:35]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[CH:34]=[CH:33][C:32]=1[CH2:38][C:39](=[O:41])[CH3:40]
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)Cc1ccc(F)cc1F
Agent: [Na+]
Product: CC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1F

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 10 mmol of (2,4-difluorophenyl)propanone are treated as described in Example 61 (method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][O:11][CH2:32][C:31]1[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:29]([C:28]([F:27])([F:41])[F:42])[CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution (0° C.) of (S)-2-t-butoxycarbonylamino-3,3-diphenylpropan-1-ol (2.04 g, 6.2 mmol, Example 1 g) in tetrahydrofuran (50 ml) and dimethylformamide (10 ml) was added sodium hydride (0.187 g, 80% suspension in oil) over 15 minutes. After an additional 10 minutes 3,5-bis(trifluoromethyl)benzyl bromide (1.14 ml) was added and the solution stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue partitioned between CH2Cl2 and water. After washing the organic phase with saturated brine and drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed on silica gel in ethyl acetate/hexane (0:100 to 50:50) to give (S)-2-t-butoxycarbonylamino-1-((3.5bis(trifluoromethyl)phenyl)methyloxy)3,3-diphenylpropane, 2.92 g.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>CCO>[CH2:32]([NH:36][C:2]1[N:10]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2CC(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1nc2c(c(=O)[nH]c(=O)n2C)n1CC(=O)c1ccccc1
Temperature: 120 °C
Yield: 44.9 %

Procedure:
A mixture of commercially available 8-bromo-3,7-dihydro-3-methyl-7-(2-oxo-2-phenylethyl)-1H-purine-2,6-dione (42, 50 mg, 0.138 mmol), diisopropylethylamine (47 μL, 0.275 mmol) and butylamine (27 μL, 0.275 mmol) in EtOH (1 mL) was heated at 120° C. for 12 h. The reaction was cooled to room temperature, the solid was filtered off, washed with water, affording the desired product as a white solid (22 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ=11.57 (s, 1H), 8.04 (d, J=7.8 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 6.99 (t, J=5.5 Hz, 1H), 5.62 (s, 2H), 3.32 (s, 3H), 3.32 (m, 2H), 1.51 (quint, J=7.4 Hz, 2H), 1.31 (sext, J=7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6): δ=192.2, 154.6, 153.0, 150.7, 150.0, 134.1, 133.8, 128.7, 127.9, 101.7, 49.5, 41.8, 31.0, 28.2, 19.2, 13.5; IR (film): ν=3361, 3008, 2827, 1681, 1485, 1425, 1230, 746 cm−1; HRMS (ESI): m/z: calcd for C18H21N5O3Na+: 378.1542, found: 378.1545.
Reaction SMILES: [C:1](OCC)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:9][C@@H:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[C:25](=[O:31])[CH2:24][C@@:23]2([CH3:32])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1.[H-].[Na+].CO>CS(C)=O>[C:1]([CH2:21][C:20](=[O:22])[C@@H:19]1[C@:23]2([CH3:32])[C@H:16]([C@H:15]3[C@H:26]([C:25](=[O:31])[CH2:24]2)[C@:27]2([CH3:30])[C@H:12]([CH2:11][C@H:10]([OH:9])[CH2:29][CH2:28]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCCC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 4 h

Procedure:
Ethyl butyrate (0.84 ml) was added to a mixture of 3α-hydroxy-5α-pregnane-11,20-dione (665 mg) and sodium hydride (150 mg.) in dry dimethyl sulphoxide (10 ml.). The mixture was stirred, under N2, for 13/4 hrs. The reaction mixture was treated with methyl alcohol to destroy excess sodium hydride, then poured into 2N-hydrochloric acid. The product was extracted with ethyl acetate and the combined extracts were washed with water, dried and evaporated. Preparative t.l.c. of the residue (859 mg.) gave two fractions. The more polar fraction was title compound (244 mg.) [α]D + 74.0°, λmax. 278 nm (ε 12,980).