Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:27]=[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:38][CH2:39][C:40]([NH:42][NH2:43])=[O:41])[CH:34]=2)[NH:29]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:43][NH:42][C:40](=[O:41])[CH2:39][O:38][C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:27])[CH:37]=[CH:36]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=O)COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(COc1ccc2[nH]c(=O)ccc2c1)NNC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a stirred solution of 2-(3,4-dichlorophenyl)acetic acid (0.440 g, 2.144 mmol) in DMF (15 mL), EDC (0.616 g, 3.22 mmol) and HOBT (0.328 g, 2.144 mmol) were added. The reaction mixture was stirred at room temperature for 10 min. To this suspension was added 2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetohydrazide (0.5 g, 2.144 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated and ice cold water was added and stirred for 10 min. The solid which separated was filtered, washed with water, and dried to afford crude 2-(3,4-dichlorophenyl)-N′-(2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetyl)acetohydrazide as a brown solid (0.7 g, 78%). LCMS: RT 1.581 min. LCMS (ES-API), m/z 420.0 (M+H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([I:21])[CH:15]=[C:16]([N+]([O-])=O)[CH:17]=1)([O-:11])=[O:10]>>[CH2:1]([O:8][C:16]1[CH:15]=[C:14]([I:21])[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(I)cc(OCc2ccccc2)c1
Yield: 54 %

Procedure:
Using the procedure described in the first paragraph of Note c. below Table I in Example 2, benzyl alcohol was reacted with 3,5-dinitroiodobenzene to give 3-benzyloxy-5-nitroiodobenzene in 54% yield, m.p. 79°-80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[C:4]([Cl:12])[CH:3]=1.C1([CH2:19][CH2:20][C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])CCCCC=1>>[Cl:12][C:4]1[CH:3]=[C:2]([CH2:19][CH2:20][C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:7]=[CH:6][C:5]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C(CCC1=CCCCC1)C1CCCC1
Reactant: CC(C)Oc1ccc(Br)cc1Cl
Product: CC(C)Oc1ccc(CCC(=O)C2CCCC2)cc1Cl

Procedure:
The ketone intermediate, was prepared analogously to Example A(27), where 4-Bromo-2-chloro-1-isopropoxy-benzene (from Step 3 below) was substituted in place of 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one in Step 1 of that example.
Reaction SMILES: CC(C)CS[S:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:22](Br)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(P(CCCC)CCCC)CCC.O>CN(C)C=O>[C:14]1([CH2:13][C:12]([NH:11][C@H:7]2[C@@H:6]([S:5][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[NH:9][C:8]2=[O:10])=[O:20])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)CSS[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)c1ccccc1
Yield: 80.7 %

Procedure:
(3R,4R)-4(2'-Methyl-n-propyldithio)-3-phenylacetamidoazetidin-2-one (0.5 g., 0.0015 mole), phenacyl bromide (1.0 g., 0.005 mole), and tributyl phosphine (0.8 ml., 0.0032 mole) were stirred in N,N-dimethylformamide (10 ml.) for 0.25 hours. The reaction mixture was poured into water (100 ml.) and extracted with ethyl acetate (3×100 ml.). The combined organic phases were washed with water (2×100 mls.) and evaporated to a yellow oil which was chromatographed on silica gel eluting with 33% ethyl acetate in benzene to yield (3R,4R)-3-phenylacetamido-4-phenacylthioazetidin-2-one (0.429 g., 78%). The constants were as described previously for compound B in Example 3.
Reaction SMILES: [CH3:1][C@H:2]1[N:14]2[C:6](=[CH:7][C:8]3[C:13]2=[N:12][CH:11]=[C:10]([CH3:15])[CH:9]=3)[C:5](=O)[NH:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C@H:2]1[N:14]2[C:6](=[CH:7][C:8]3[C:13]2=[N:12][CH:11]=[C:10]([CH3:15])[CH:9]=3)[CH2:5][NH:4][CH2:3]1
Reactant: Cc1cnc2c(c1)cc1n2[C@H](C)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cnc2c(c1)cc1n2[C@H](C)CNC1

Procedure:
This compound was prepared in analogy to Example 3, intermediate l) from (R)-4,7-dimethyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one and lithium aluminium hydride. The product was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:methanol (9:1, then 3:1) as eluant.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17]=[O:18])[NH:14][C:13]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:17][OH:18])[NH:14][C:13]1=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC[C@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a solution of (3R,4R)-3-benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (850 mg) in methanol (17 ml) was added sodium borohydride (123 mg) at 0° C. and the mixture was stirred for 15 minutes at 0° C. Acetic acid (0.37 ml) was added to the mixture at 0° C. After stirring for 15 minutes at 0° C., the mixture was evaporated in vacuo. The residue was chromatographed on silica gel (17 g) eluting with a mixture of methylene chloride and methanol (20:1-10:1) to give a crystalline solid. This crude crystals were washed with ether and dried over phosphorous pentoxide to give (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (748 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH2:31][CH3:32])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH2:31][CH3:32])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1oc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Yield: 90.9 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-5-propyl-3-methoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate obtained in Example (116d) (0.22 g, 0.44 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (2 mL) and THF (3 mL), to obtain 176 mg of the title compound as a colorless solid (91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33]([OH:35])[CH3:34]>>[CH2:33]([O:35][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1)[CH3:34]
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Cl)n1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1nc(C)cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)n1
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of 2-chloro-6-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (40 mg, 0.1 mmol, Step-1 of Example 456, single enantiomer) and cesium carbonate (50 mg, 0.15 mmol) in ethanol (2 mL) is heated by microwave irradiation at 160° C. for 1 hour. After cooled to room temperature, the mixture is concentrated under reduced pressure. The residue is suspended in ethyl acetate and filtered through a short column of amine gel eluting with ethyl acetate. The filtrate is concentrated and then by preparative LC-MS to give 17 mg (41% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:8]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:29])=[CH:9][C:8]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1CCCOC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1CCCOC
Reaction time: 1 h

Procedure:
To 2.21 g (6.01 mmol) of the above prepared [4-tert-butoxycarbonylamino-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester, dissolved in 18 ml of abs. DMF, was added at 0° C. 0.313 g of NaH (60% in mineral oil, 1.3 eq.). 5 Min. later, 0.75 ml (2 eq.) of MeI was added and the reaction allowed to proceed for 10 Min. at 0° C. and for 1 h at ambient temperature. Pouring onto crashed ice/KHSO4 solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), yielded 1.55 g of the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH:20]=[O:21])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20][OH:21])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: COCCOCc1c(C=O)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCOCc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
To a cold (0° C.), stirred solution of 1.05 g of N-(4-chlorobenzyl)-2-formyl-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 20 mL of CH2Cl2 is added 0.67 mL of acetic acid and 1.5 g of sodium triacetoxyborohydride. The mixture is allowed to warm to room temperature and stirred for 2 h, then partitioned between CH2Cl2 and aqueous NaHCO3. The organic phase is dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 2.5-4% MeOH in CH2Cl2 affords 1.08 g (100%) of the title compound as a yellow crystalline solid. Recrystallization from acetonitrile affords white spars.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1>[F:21][C:4]1[CH:3]=[C:2]([NH:30][C:27]2[N:26]=[CH:25][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:29][N:28]=2)[CH:7]=[CH:6][C:5]=1[C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: Nc1ncc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Br)cc2F)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2F)C1
Temperature: 100 °C
Yield: 82.5 %

Procedure:
To a 25 ml glass vial was added (+)-(R)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (300 mg, example 192(f)) and 5-trifluoromethyl-pyrimidin-2-ylamine (156 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (58.3 mg), tris(dibenzylideneacetone)dipalladium(0) (30.5 mg) and sodium tert-butoxide (89.8 mg) were then added. The vial was capped and heated at 100° C. for 2 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to afford (R)-tert-butyl 2-(2-fluoro-4-(5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (304 mg, 83%) as an amorphous yellow solid. MS (ISP): 441.2 ([M−H]−).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:10]N1C(=O)CCC1=O.O>O1CCCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.5 %

Procedure:
To a solution of 2,3-dihydrobenzofuran (15.0 g, 125 mmol) in tetrahydrofuran (300 mL) was added N-bromosuccinimide (24.5 g, 138 mmol) at 0° C. The reaction solution was stirred at room temperature for 50 minutes, then, water was added, the solution was extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel column chromatography (hexane), and the title compound (24.0 g, 97%) was obtained as a colorless oily substance.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]4[CH:19]=[C:20]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:21]([N:23]([CH:25]4[CH2:27][CH2:26]4)[CH3:24])=[O:22])[CH:15]=3)[N:10]([CH3:32])[C:9]2=[O:33])=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(O)(C(F)(F)F)=O>[CH:25]1([N:23]([CH3:24])[C:21](=[O:22])[C:20]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH3:32])[C:9](=[O:33])[N:8]=[CH:17]4)[CH:19]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc(CN2Cc3cc(-c4cc(C(=O)N(C)C5CC5)ccc4C)ccc3N(C)C2=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N(C)C2CC2)cc1-c1ccc2c(cnc(=O)n2C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 3-(3-(4-methoxybenzyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-N-cyclopropyl-N,4-dimethylbenzamide (0.445 g, 948 μmol) in TFA(4.00 ml) in a microwave reaction vessel was sealed and heated at 100° C. for 20 min under microwave irradiation. After cooling, the mixture was filtered through a short path of Celite and the filter cake was washed with EtOAc (3×10 mL). The mixture was concentrated and the crude product was taken up to a solution of DCM (5.00 ml), treated with DDQ (215 mg, 948 μmol) at 0° C. for 10 min then stirred at RT for 1 h. The reaction was quenched with NaHCO3(aq) and water (10 mL each) and the separated aqueous layer was extracted with DCM (5 mL×3). The combined organic phases were washed with 1N NaOH(aq), brine, dried (Na2SO4), and concentrated to give a crude residue. Flash column chromatographic purification (5% MeOH in DCM) of the residue provided the title compound N-cyclopropyl-N,4-dimethyl-3-(1-methyl-2-oxo-1,2-dihydroquinazolin-6-yl)benzamide as a pale tan solid. MS m/e 308 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Pd].CO>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
A mixture of t-butyl N-(5-benzyloxy-2-nitrophenyl)-N-methylcarbamate (15 g), palladium on carbon (3 g, 10%), toluene (150 ml) and methanol (150 ml) was stirred under a hydrogen atmosphere at room temperature for 12.5 hours. The palladium on carbon was filtered and the filtrate was concentrated to afford the title compound (12.3 g, brown oil, Rf=0.15: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=4 : 1 as the eluant).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:39])(=[O:38])[NH:11][C:12](=[O:37])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH3:24])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:31]1([C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:14]=[CH:13][C:12]([NH:11][S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=3)(=[O:39])=[O:38])=[O:37])=[CH:16][CH:17]=2)=[C:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH3:24])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1)c1ccccc1

Procedure:
Prepared by hydrolyzing 1s using 4N aq sodium hydroxide (2 eq) in 4:1 dioxane/methanol at room temperature. Yield (82%); 1H NMR (d6-DMSO) δ 13.48 (br s, 1H), 12.36 (br s, 1H), 8.10 (d, J=8.0 Hz, 2H), 8.02 (d, J=8.0 Hz, 2H), 7.39-7.07 (m, 13H), 6.84 (d, J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.7 Hz, 2H), 0.82 (t, J=7.7 Hz, 3H); APcI m/z: 538 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=O>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:11]([CH3:16])([CH3:12])[CH3:9])=[O:18])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: O=CC1CCN(C(=O)O)CC1
Product: CCN1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 78 %

Procedure:
In operating analogously to preparation LXXIII, starting with N-ethylpiperazine and the t-butyl ester of 4-formyl-1-piperidinecarboxylic acid, the product sought after is obtained as a colourless oil (yield=78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=O)=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:26][NH2:27].CO>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:17])[N:27]([CH3:26])[CH2:19][C:13]=3[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Solvent: CO
Product: CN1CC2=C(C1=O)C(c1ccc(F)c(Br)c1)C1=C(COCC1=O)N2

Procedure:
A solution of the product from Example 25B (0.16 g, 0.34 mmol) and 2M methyl amine in methanol (3.5 mL, 7.0 mmol) was stirred at ambient temperature for 16 hours and concentrated. Purification of the residue on silica gel (5% and then 10% methanol in methylene chloride) provided an oil which was crystallized from ethanol, collected by filtration and dried to yield the title compound (0.016 g) as a white solid.
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.N1C=CC=CC=1>CCOCC>[C:1]1([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: OP(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
Diphenylphosphinous acid chloride [(C6H5)2PCl, 55 g.] was added to a solution of phenol (21.6g) and pyridine (18 g.) in 250 ml. of dry ether at 5°C. with stirring. After standing overnight, the precipitated pyridinium chloride was removed by filtration and the filtrate distilled. The phenyl ester of diphenylphosphinous acid [(C6H5)2POC6H5 ] obtained weighed 54 g. and boiled at 145°C. at 0.1 mm.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:31])[CH2:20][C:21]3[N:22]=[N:23][N:24](C(OC)(C)C)[N:25]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([N:44]=[C:45]=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1>C1COCC1>[F:32][C:33]([F:47])([F:48])[C:34]1[CH:35]=[C:36]([NH:44][C:45](=[O:46])[N:11]([CH:8]2[CH2:9][CH2:10][CH:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:6][CH2:7]2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:31])[CH2:20][C:21]3[N:25]=[N:24][NH:23][N:22]=3)=[CH:15][CH:14]=2)[CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(C)(C)n1nnc(CC(=O)c2ccc(CNC3CCC(C(C)(C)C)CC3)cc2)n1
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
1-{4-[(4-tert-Butylcyclohexylamino)methyl]phenyl}- 2-[2-(1-methoxy-1-methylethyl)-2H-tetrazol-5-yl]ethanone (320 mg, 0.75 mmol) was dissolved in THF (5 ml), and 3,5-bis(trifluoromethyl)phenyl isocyanate (191 mg, 0.75 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then taken to dryness by rotary evaporation. The residue was stripped twice from acetonitrile to give 450 mg (88%) of title material.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][NH2:10]>>[CH3:8][N:9]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: CNN
Reactant: Clc1cnccn1
Product: CN(N)c1cnccn1
Yield: 35.9 %

Procedure:
2-Chloropyrazine (1 g, 8.3 mmol) and methylhydrazine (1.31 mL, 25 mmol) were mixed together in a flask fitted with a water condenser. After a few minutes an exotherm was observed. After 16 h the excess methylhydrazine was removed under reduced pressure. The cooled residue was stirred with aqueous sodium hydroxide solution (20 ml of 20%), and the resulting solution was extracted with ether (6×100 ml). The combined extracts were dried (K2CO3) and concentrated to give a light orange solid 370 mg of N-Methyl-N-pyrazin-2-yl-hydrazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[S]>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4CC=CCC4)cc3c2c1C
Agent: [S]
Solvent: CS(C)=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(-c4ccccc4)cc3c2c1C
Yield: 11.2 %

Procedure:
435 mg (1.3 mmol) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated in 10 ml of dimethyl sulfoxide with 125 mg of sulfur under nitrogen for 2 hours to 180° C. After evaporation under vacuum, the reaction mixture is distributed in methylene chloride/saturated sodium bicarbonate solution. The methylene chloride phase is evaporated and the residue chromatographed over silica gel with toluene:glacial acetic acid:water=10:10:1 as the eluent. After evaporation of the corresponding fractions and mixing with hexane under agitation, 48 mg (8.4% of theory) of 6-phenyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester is obtained, mp 241°-242° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH:7]=1)[CH2:8][Br:11]
Reactant: COc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Br)cc(CBr)c1

Procedure:
A mixture of 5-bromo-3-methoxytoluene (20 g, 0.1 m), N-bromosuccinimide (17.8 g, 0.1 m) and dibenzoyl peroxide in carbon tetrachloride (200 ml) is heated to reflux and irradiated with a sunlamp. The mixture is cooled, filtered and concentrated in vacuo to give 5-bromo-3-methoxybenzyl bromide.