Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[C:11]=1[CH3:12].[N+:13]([O-])([OH:15])=[O:14]>O>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[C:11]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)ccc2oc(=O)[nH]c12
Solvent: O
Product: Cc1c(F)c([N+](=O)[O-])cc2oc(=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
5-Fluoro-4-methyl-2-benzoxazolone (Preparation A, 2.01 g, 12 mmoles) was treated with concentrated nitric acid (24 ml) at room temperature under stirring. The mixture was heated to 50° C. and stirring continued for 20 minutes. Ice and water were added to the mixture and the resulting solids were collected, and washed with water and then with ethanol. The crude product was dried under reduced pressure and recrystallized from ethanol to give 1.84 g (72%) of the title compound: m.p. 194°-196° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([S:19][CH3:20])[N:16]=[C:17](Cl)[C:12]=2[C:11](=[O:21])[CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.[NH2:35][NH2:36]>O1CCOCC1>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([S:19][CH3:20])[N:16]=[C:17]([NH:35][NH2:36])[C:12]=2[C:11](=[O:21])[CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Reactant: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(NN)c2C1=O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Ethyl 8-benzyl-4-chloro-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate from step-1 (48 g, 0.122 mol) in 1,4-dioxane (300 mL), and triethylamine (20.5 mL, 0.147 mol) was added hydrazine hydrate (6.73 g, 0.134.6 mol). The reaction mixture was stirred at room temperature for 5-6 h. After completion of the reaction, dioxane was evaporated under vacuo, and water (250 mL) was added to the reaction mixture and was extracted with dichloromethane (200 mL×3). The combined dichloromethane layer was washed with water (500 mL) followed by brine (500 mL). The dichloromethane layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude ethyl 8-benzyl-4-hydrazinyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate as an oil that was used for next step without further purification.
Reaction SMILES: [SiH](CC)(CC)CC.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([OH:25])=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=O)[CH:14]=1.C(S(O)(=O)=O)(F)(F)F>C(O)(C(F)(F)F)=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([OH:25])=[C:13]([CH2:15][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=2)[CH:14]=1
Reactant: CCc1ccc(C(=O)c2cc(Cl)ccc2O)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cc2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred 0° C. solution of Et3SiH (2.26 ml, 14.2 mmol) and (5-chloro-2-hydroxyphenyl)(4-ethylphenyl)methanone (1.944 g, 7.08 mmol) in 10 mL of TFA was added CF3SO3H (30 μL) at a rate to keep the temperature at about 0° C. After complete addition, the mixture was warmed to room temperature and stirred overnight at room temperature. After the volatiles were evaporated under reduced pressure, the residue was partitioned in ethyl acetate and water. The organic layer was separated and washed with water, aq Na2CO3, brine then dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (PE:EA=10:1) to give the target compound (1.659 g).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccc(F)cc3)cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccc(F)cc3)C=C1C(C)=O)C2=O

Procedure:
The title compound 155 is prepared according to the procedure reported in Example 39.1 with compound 129 (75 mg, 0.15 mmol) and BNAH (32 mg, 1 equiv) as reactants. Yellow solid. (Yield 31.4 mg, 50%).
Reaction SMILES: [Li]CCCC.[Li][Li].[Cl-:8].[Cl-].[Cl-].[Cl-].[Zr+4:12].[Li].[Li].[CH:15]1([C:20]([CH:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)([CH2:22][CH2:23][CH2:24][O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16]1>CCCCCC.C1(C)C=CC=CC=1>[Cl-:8].[Cl-:8].[Zr+2:12].[CH:30]1([C:20]([CH:15]2[CH:16]=[CH:17][CH:18]=[CH:19]2)([CH2:22][CH2:23][CH2:24][O:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH3:21])[CH:31]=[CH:32][CH:33]=[CH:34]1
Reactant: [Zr+4]
Agent: CC(CCCO[Si](C)(C)C)(C1C=CC=C1)C1C=CC=C1
Agent: [Cl-]
Agent: [Li]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Zr+2]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The previously distilled ligand (20.2 g, 0.07 mol) was placed in a 500 ml Schlenk flask and dissolved in dry hexane (250 ml). n-BuLi 1.6 M in hexane (87.3 ml 0.14 mol) was dropwise added is solution at 5° C. The resulting white suspension was heated to 75° C. for a 6 h period until the total formation of the dilithium salt was confirmed by NMR. The mixture was left to cool down to room temperature, filtered and dried under vacuum. ZrCl4 (16.28 g, 0.07 mol) was placed in the 500 Schlenk flask and toluene (200 ml) was added, and, at the same time, toluene (200 ml) was added to 2,2-bis(cyclopentadienyl)-5trimethylsiloxypentane dilithium salt. Both suspensions were cooled to −78° C. and the dilithium salt slurry was, via cannula, added to the ZrCl4 one. The resulting off-white suspension was allowed to warm to room temperature and stirred for 16 h. The resulting orange-red suspension was filtered and the cake washed with toluene (100 ml). The solvent was removed under vacuum and the resulting oily solid was repeatedly extracted with hexane, concentrated to 1/10 in volume and cooled to −30° C. to afford yellow crystals of the product (6.8 g, 22% yield). 1H NMR (CDCl3): Λ6.70 (C5H4, d, 4H), 5.82 (C5H4, d, 4), 3.75 (CH2, t, 2H), 2.28 (CH2, m, 2H), 1.83 (CH2, m, 2H), 1.80 (CH3, s, 3H), 0.18 ((CH3)3, s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].Cl.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 10.0 g (45.4 mmol) 4-methoxy-3-trifluoromethyl-benzoic acid and 75 g (649 mmol) pyridine hydrochloride was stirred for 5 hours at 180° C. under nitrogen gas. The reaction mixture was then poured onto 1 L of 10% citric acid solution, extracted with 500 ml EtOAc, the organic phase washed with 1 L water, dried and evaporated down under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[C:4]1=[O:17].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH2:2][N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[C:4]1=[O:17]
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)N(CO)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(CO)C1=O

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-2-(hydroxymethyl)-8-methyl-2H-pyrido[4,3-b]indol-1(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18]CC)=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27]C)=[O:26])[CH:3]=1.CO.[OH-].[Na+].O>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1
Reactant: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c2nc(C(=O)O)cc(Cl)c2cc2c(=O)cc(C(=O)O)oc12
Yield: 65.5 %

Procedure:
Ethyl 6-chloro-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate (1.313 g) was suspended in refluxing methanol (300 mls) and 0.1 M sodium hydroxide solution (65 mls) was added dropwise, with stirring. The whole was then refluxed for ten minutes, cooled, poured into water and acidified. The precipitated product was extracted into ethyl acetate, washed with water, dried with magnesium sulphate, filtered and volatiles removed in vacuo, affording 1.05 g of the crude sub-title compound as a yellow solid. This yellow solid was dissolved in sodium bicarbonate solution, filtered and the filtrate acidified. The precipitated product was collected by filtration, washed with water and dried to give 0.77 g of the sub-title compound. MP 340° C.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:13][N:6]2[C:7](=[O:12])[CH2:8][CH2:9][NH:10][CH2:11][C@@H:5]2[CH2:4]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[OH:2][C@H:3]1[CH2:13][N:6]2[C:7](=[O:12])[CH2:8][CH2:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=3)[CH2:11][C@@H:5]2[CH2:4]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: O=C1CCNC[C@@H]2C[C@@H](O)CN12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@@H](O)CN12
Temperature: 100 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (8R,9aS)-8-hydroxyoctahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (90 mg, 0.435 mmol, Part A), 2-bromo-5-(trifluoromethyl)pyridine (148 mg, 0.635 mmol) and sodium carbonate (138 mg, 1.306 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100° C. overnight. The mixture was purified by chromatography on silica gel (ethyl acetate/methanol=15:1) to give 135 mg (98% yield) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (m, 1H), 2.09 (m, 1 H), 2.50-2.66 (m, 2 H), 3.08 (m, 1 H), 3.35 (m, 2 H), 3.50 (m, 1 H), 3.98 (m, 2 H), 4.20 (m, 1 H), 4.44 (m, 1 H), 4.55 (m, 1H), 4.88 (br s, 1H), 7.01 (d, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 8.43 (s, 1H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C([C:15]([O-:17])=[O:16])=CC=CC=1O.[K+].C(C1C(CC2C=CC=CC=2)=C(C)C=CC=1)C1C=CC=CC=1.C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Cc1c(O)cccc1C(=O)[O-]
Agent: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 81.1 %

Procedure:
A pressure vessel was charged with 4.71 g of phenol, 17.56 g of potassium ortho-cresolate being in a dry powder form and 43 ml of NeoSK 1400 (a dibenzyltoluen mixture medium produced by Soken Chemical K.K.). With stirring, reaction was carried out at a carbon dioxide pressure of 3 kg/cm2 (G) and at 270° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 81.1% on the basis of phenol.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C:29]12([CH2:39][S:40]([OH:43])(=[O:42])=[O:41])[C:36]([CH3:38])([CH3:37])[CH:33]([CH2:34][CH2:35]1)[CH2:32][C:30]2=[O:31]>CO>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH3:37][C:36]1([CH3:38])[C@:29]2([CH2:39][S:40]([OH:43])(=[O:42])=[O:41])[C:30]([CH2:32][C@H:33]1[CH2:34][CH2:35]2)=[O:31]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CO
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Temperature: 10 °C

Procedure:
12.25 g (0.03 mol) of amlodipine was dissolved in 50 ml of methanol, cooled to 10° C., and a solution of 7.8 g (0.336 mol) of (±)-10-camphor sulfonic acid (Aldrich) in 19.5 ml of methanol was gradually added thereto. 16.0 g (yield: 83.2%) of the title compound in the form of a white crystal was obtained by using the same method described in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+]=[N-])[C@@H:9]([NH:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:7]=1)=[O:5])[CH3:2].O.C(O)(=O)C.C(P(CCCC)CCCC)CCC>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH2:12])[C@@H:9]([NH:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1
Temperature: 3 °C
Reaction time: 1.5 h

Procedure:
To a solution of 50.0 g (0.147 mol) of 30, 300 mL of EtOH, 50 mL of water and 0.09 g of acetic acid in a nitrogen-purged 1000 mL glass reactor fitted with a mechanical stirrer, a condenser, and a 250 mL dropping funnel was added a solution of 31.4 g (0.155 mol) of tributylphosphine in 150 mL EtOH at a temperature of 5° C. (+/−5° C.) over a period of 30-90 min. The reaction temperature was maintained at this temperature by slight cooling of the jacket (ca. 3° C.). The funnel was rinsed with 20 mL of EtOH. The clear reaction mixture was stirred for additional 90 min at 5° C. (+/−5° C.) under slight jacket cooling. Subsequently the temperature was raised within 30-60 min to 20-25° C. and the solution was stirred for another 3 h (nitrogen evolution). After the reaction was finished (HPLC assay) 0.18 g of acetic acid were added to the clear solution and the mixture was concentrated to near dryness under reduced pressure (300 to 50 mbar) at a maximum temperature of 60° C. and a maximum jacket temperature of 75° C. The oily residue (80-100 mL) was diluted with 160 mL of EtOH, the resulting solution was then again concentrated following the method described above. The oily residue was dissolved in EtOH up to a volume of 250 mL. The water content of this solution was determined by KF(Karl Fischer) titration to be less than 1.0% wt. %. Yield: 44.4 g (97% area by HPLC) of 32 in EtOH solution.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][CH:43]([CH3:62])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:52]=2)[NH:47][CH:46]=1>>[CH2:55]([O:54][C:51]1[CH:52]=[C:53]2[C:48](=[CH:49][CH:50]=1)[NH:47][CH:46]=[C:45]2[CH2:44][CH:43]([NH:42][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[CH3:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(N)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: CC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)NC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 33.6 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (68 mg, 0.12 mmol) and 3-(2-aminopropyl)-5-(benzyloxy)-indole hydrochloride (46 mg, 0.15 mmol) according to Method C with HPLC purification to give the title compound (32 mg) as a diasteromeric mixture. IR (KBr) 3409, 1681, 1652 cm−1; HRMS m/z 792.3360 (calc. of monoisotopic mass for C44H48N4O10 gives 792.3370).
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH2:9][CH2:10][N:11]([CH2:25][CH2:26][Br:27])[C:12]1[CH:17]=[CH:16][C:15]([NH:18]C(NCCBr)=O)=[CH:14][CH:13]=1>CCOCC>[Br:8][CH2:9][CH2:10][N:11]([CH2:25][CH2:26][Br:27])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1
Reactant: O=C(NCCBr)Nc1ccc(N(CCBr)CCBr)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1ccc(N(CCBr)CCBr)cc1
Yield: 95 %

Procedure:
2HCl (2.93 g) was reacted with triethylamine (2.90 g) in ether (150 ml). The reaction mixture was filtered, and β-bromoethyl isocyanate (1.23 g) was added to the filtrate to give a white solid (3.32 g; melting point 103°-105° C.). The infrared absorption spectrum of the solid was as shown in FIG. 2. It was very similar to the infrared absorption spectrum of N-[p-bis(β-chloroethyl)aminophenyl]-N'-(β'-chloroethyl)urea obtained in Example 1, and showed a strong absorption based on the NH linkage at 3300 cm-1 and a strong absorption based on the carbonyl linkage of the ureido group at 1625 cm-1. The elemental analysis values were C 33.44%, H 3.47%, and N 8.84% which agreed with the calculated values for the composition formula C13H18N3OBr3 (472.04) which were C 33.908%, H 3.84%, N 8.90%. Its mass spectrum showed M⊕ at m/e=472 and peaks corresponding to [M⊕ -Br] at m/e=393 and 392. The foregoing results clearly show that the resulting white solid is N-[p-bis(β-bromoethyl)aminophenyl]-N'-(β'-bromoethyl)urea (designated as compound No. 1). The yield was 95.0%. ##STR13##
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)CN(Cc2ccccc2)CCC1O
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.3 g, 8.13 mmole) was added to the stirred solution of 1-benzyl-3,3-diethylpiperidin-4-one (4.0 g, 16.26 mmole) in methanol (22 ml) at 0-5° C. over a period of 15 min, and stirring was continued for 30 min. The reaction mixture was concentrated to dryness, triturated with water (25 ml) and extracted with ethyl acetate (2×100 ml). The extract was dried (sodium sulphate) and concentrated to dryness to furnish 1-benzyl-3,3-diethyl-4-hydroxy-piperidine as oil. Yield 3.9 g (97%), C16H24NO, m/z 248 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(COC)OC>[C:26]1([S:32]([N:11]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cnc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a stirred mixture of 10.0 g (0.04 mole) of 4,5-bis(4-fluorophenyl)imidazole and 4.8 g (0.043 mole) of potassium t-butoxide in 150 ml glyme at 0° was added dropwise a solution of 7.6 g (0.043 mole) of benzenesulfonyl chloride in 25 ml glyme. The mixture was stirred at 0° one hour, then at room temperature overnight. The mixture was poured into ice water and the solid was collected and air dried to give 15.2 g, mp 172°-5°. Recrystallization from toluene/methylcyclohexane gave 12.3 g of 1-benzenesulfonyl-4,5-bis(4-fluorophenyl)imidazole as a white solid, mp 181°-2°.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[F:11])[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(F)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(F)c1
Yield: 82 %

Procedure:
Reduction of 3,4-difluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (82% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 3.98 (2H, s, NCH2), 5.73 (1H, broad s, NH), 7.04–7.23 (3H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 139–142° C. (dec.). Anal. calcd. for C8H9F2NO2—HCl: C, 45.83; H, 4.80; N, 6.68. Found: C, 45.96; H, 4.93, N, 6.67.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[F:1][C:2]1[CH:3]=[C:4]([NH:11][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
4-Fluoroanthranilic acid (1.5 g) and sodium hydroxide (0.4 g) were stirred in cold water (100 ml) at ca. 5°. Benzenesulphonyl chloride (1.25 ml) was added and the mixture was stirred overnight, acidified and extracted with dichloromethane. The extracts were washed, dried and evaporated to give 4-fluoro-N-(phenylsulphonyl)anthranilic acid, mp 158°-9°. (Compound 14).
Reaction SMILES: C([N:8]1[CH:13]([C:14]#[N:15])[CH2:12][CH2:11][CH2:10][C:9]1([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]#[N:17])C1C=CC=CC=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:17][CH2:16][C:9]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:10][CH2:11][CH2:12][CH:13]([CH2:14][NH2:15])[NH:8]1
Reactant: CC(C)(C)OC(=O)CC1(C#N)CCCC(C#N)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1CCCC(CN)(CC(=O)O)N1

Procedure:
A solution of 6.00 mmol of tert-butyl (1-benzyl-2,6-dicyanopiperidin-2-yl)acetate in 40 ml of methanol is admixed with 2 ml of 37% strength aqueous hydrochloric acid and 0.600 g of 10% Pd/C. The reaction mixture is hydrogenated with 4 bar of hydrogen at 22° C. for 18 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. From the residue the crude title compound is identified on the basis of the Rf value. The title compound is used without further purification in the next stage.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[C:5]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([CH3:20])[CH:3]=1.Cl.S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([Cl:25])[C:7](=[O:12])[C:6]=2[C:5]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([CH3:20])[CH:3]=1
Reactant: CCOC(=O)CCc1c(C)cc(Cl)c2c1C(=O)CCC2
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1c(C)cc(Cl)c2c1C(=O)C(Cl)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of ethyl 3-(4-chloro-2-methyl-8-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)propanoate (5.70 g, 20.3 mmoles) in CH2Cl2 (20 ml) was saturated with dry gaseous HCl and sulfuryl chloride (16.4 ml, 27.5 g, 203 mmoles) was added dropwise and stirred at room temperature for 2 hours. The solvent and excess sulfuryl chloride were evaporated in vacuo then chased with dry toluene two times to leave 6.40 g of title compound as a gum. Exact mass calculated for C16H17O3Cl (parent-HCl): 292.0866; Found: 292.0869