Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].O.O.[N+:4]([O-:7])([O-:6])=[O:5].[Pd+2:8].[N+]([O-])([O-])=[O:10].[O-2].[O-2].[O-2].[Al+3:16].[Al+3]>O>[Pd:8].[N+:4]([O-:7])([O-:6])=[O:5].[O-2:10].[O-2:1].[O-2:5].[Al+3:16].[Al+3:16]
Reactant: [Pd+2]
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Al+3]
Agent: [O-2]
Product: [Pd]

Procedure:
Palladium (II) nitrate trihydrate (0.270 g) was dissolved in water (21.0 ml) and added to gamma-alumina (5.0 g, from calcination of Catapal SB boehmite alumina in air at 580° C.) with stirring. Water was slowly removed in vacuo keeping the catalyst temperature about 55° C. and the catalyst was then dried further at 100° C. for 12 hours.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CC1(C)[NH:58][CH2:57][CH2:56][O:55]1>C1COCC1.C(OCC)(=O)C>[OH:55][CH2:56][CH2:57][NH:58][C:14]([C:10]1[CH:9]=[C:8]([O:7][C:6]2[CH:17]=[CH:18][C:3]([NH:2][CH3:1])=[C:4]([N+:19]([O-:21])=[O:20])[CH:5]=2)[CH:13]=[CH:12][N:11]=1)=[O:16]
Reactant: CNc1ccc(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Reactant: CC1(C)NCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a suspension of the 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3 eq) were added. The suspension was stirred for 10 minutes whereupon 2,2-dimethyl-oxazolidine (1.1 eq) was added and the solution is allowed to stir overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers combined, dried over MgSO4, filtered, and concentrated. LCMS m/z 333.2 (MH+), tR=2.1 min.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[N:20]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
[(5R)-3-(4-Iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (27 g, 68 mmol) was dissolved in dimethylacetamide (300 ml). Sodium azide (13.1 g, 202 mmol) was carefully added, and the solution was heated to 80° C. for 3 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 ml), washed with water (2×), brine, and dried over sodium sulfate. Flash chromatography with 0-1% methanol in dichloromethane as eluent gave the desired product (19 g).
Reaction SMILES: C(C1C=CC([CH:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)=[CH:13][CH2:12]2)=CC=1)CCC.[CH2:26]([C:30]1[CH:35]=[CH:34][C:33](C2CCC(=O)CC2)=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29].BrC1C=C(F)C(F)=C(F)C=1>>[CH2:26]([C:30]1[CH:35]=[CH:34][C:33]([C:13]2[C:14]([C:17]3[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=3)=[CH:15][CH:16]=[CH:11][CH:12]=2)=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1ccc(C2CCC(=O)CC2)cc1
Reactant: CCCCc1ccc(C2CC=C(c3cc(F)c(F)c(F)c3)CC2)cc1
Agent: Fc1cc(Br)cc(F)c1F
Product: CCCCc1ccc(-c2ccccc2-c2cc(F)c(F)c(F)c2)cc1

Procedure:
Using 1-[4-(4-butylphenyl)cyclohexen-1-yl]-3,4,5-trifluorobenzene obtained by reacting 4-(4-butylphenyl)-cyclohexanone with 1-bromo-3,4,5-trifluorobenzene, as a starting raw material, 4"-butyl-3,4,5-trifluoroterphenyl was obtained in the same manner as in Example 3.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH:9]([C:22]([OH:24])=O)[CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:28](OC1C=CC=CC=1)=[O:29].Cl>O1CCCC1.O>[O:29]=[C:28]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C@@H:9]2[C:22]([O:13][C:11](=[O:12])[C@@H:10]2[N:14]1[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
220 g (0.67 mol) of meso-2,3-bis(benzylamino)succinic acid were placed under a nitrogen atmosphere in a 2 l flask fitted with two dropping funnels, a pH electrode, and a stirrer. The meso-2,3-bis(benzylamino)succinic acid was then suspended, while stirring, in 800 ml of tetrahydrofuran and 400 ml of deionized water, and brought into solution by the addition of 108 ml of a 50% potassium hydroxide solution. 200 ml of 2.4 mole eq. phenyl chloroformate were added dropwise to the solution within 3.5 hours. The pH was maintained between 9 and 11 during the addition of phenyl chloroformate by the successive addition of 50% potassium hydroxide solution and the internal temperature was maintained between 30° C. and 35° C. After the addition was completed, the mixture was stirred at about 30° C. for 2 hours and then the pH was adjusted to about 7-8 with concentrated hydrochloric acid. The aqueous solution was extracted twice with toluene and 500 ml of tetrahydrofuran were added to the combined aqueous phases. The mixture was adjusted to a pH of 1.0 with 37% hydrochloric acid, and the aqueous phase was separated off. 400 ml of toluene were added to the tetrahydrofuran phase and the tetrahydrofuran was distilled off under reduced pressure. The remaining water was removed azeotropically with toluene. After the addition of 700 ml of toluene and 130 ml of acetic anhydride, the mixture was heated to 80° C. After the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride had crystallized out, the obtained suspension was cooled to 10° C. within 2 hours in order to complete the crystallization. The crystalline 2-oxo-1,3-dibenzyl-cis4,5-imidazolidinedicarboxylic acid anhydride was filtered off and washed twice with toluene. After drying to constant weight under reduced pressure, there were obtained 173.6 g (78% yield) of 2-oxo-1,3-dibenzyl-cis4,5-imidazolidinedicarboxylic acid anhydride in the form of an analytically pure, colourless solid, with a melting point of 240.2° C. 3.0 g of 2-oxo-1,3-dibenzylamino-cis4,5-imidazolidinedicarboxylic acid anhydride were further obtained on evaporation of the main solution.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[C:13](=O)(OC)OC.C(P(CCCC)CCCC)CCC>>[CH3:13][O:3][C:2]1[C:1]([O:11][CH3:12])=[CH:10][C:6]([CH2:7][CH:8]=[CH2:9])=[CH:5][CH:4]=1
Reactant: COC(=O)OC
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: CCCCP(CCCC)CCCC
Product: C=CCc1ccc(OC)c(OC)c1
Yield: 88 %

Procedure:
33 parts of eugenol, 50 parts of dimethyl carbonate and 2 parts of tri-n-butylphosphine are kept for 15 hours at 190° C. Working up takes place as described in Example 24. 31 parts (88% of theory, based on converted eugenol) of eugenol methyl ether of boiling point 69°-70° C./0.13 mbar are obtained. The conversion is virtually quantitative.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1>ClCCl>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[CH3:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a suspension of potassium carbonate (126.01 g, 911.76 mmol, 1.30 equiv) and 2-amino-3-methyl-5-chloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (211 g, 701 mmol) in dichloromethane (300 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (256.78 g, 771.49 mmol, 1.10 equiv.) in dichloromethane (200 mL) at room temperature. After 2 h at this temperature, the solids were filtered off. The resulting filtrate was washed with water and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diisopropyl ether to yield the title compound (344.2 g, 85%).
Reaction SMILES: CC(C)=O.C(=O)=O.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)([O-:10])=[O:9].Cl[C:21]1([S:27][CH3:28])C=CN=[CH:23][NH:22]1.[C:29](#[N:31])[CH3:30].C1COCC1>>[CH3:28][S:27][C:21]1[N:22]=[C:23]([N:15]2[C:16]3[C:12](=[C:11]([N+:8]([O-:10])=[O:9])[CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)[CH:30]=[CH:29][N:31]=1
Reactant: CC#N
Reactant: CSC1(Cl)C=CN=CN1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CSc1nccc(-n2ccc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium(bistrimethylsilyl)amide (1 M in THF, 26.42 mL) was slowly added to a cooled (acetone/dry-ice bath) solution of 4-nitroindole (4.2 g, 25.9 mmol) in a mixture of acetonitrile/THF (2/1, 75 mL) and the resulting mixture was stirred for 1 hour. 4-Chloro-4-methylthiopyrimidine (4.202 g, 26.2 mmol) was then added and the reaction mixture was warmed to RT and stirred for 21 h. The resulting mixture was evaporated under reduced pressure and the solid residue was triturated with a mixture of hexane/EtOAc/Et2O (5/1/1). The solid was collected by filtration, washed and dried under reduced pressure to give 2.56 g of 1-(2-methylsulfanyl-pyrimidin-4-yl)-4-nitro-1H-indole which was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:12]1[CH2:16][CH:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:14][C:13]1=[O:27])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:15]2[O:14][C:13](=[O:27])[N:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH2:16]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(OCC2CN(C(C)CO[Si](C)(C)C(C)(C)C)C(=O)O2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(OCC2CN(C(C)CO)C(=O)O2)cc1
Yield: 111 %

Procedure:
A procedure similar to that described in Preparation 5(b) was repeated, except that 1.52 g of 3-(2-t-butyldimethylsilyloxy-1-methylethyl)-5-(4-methoxyphenoxymethyl)oxazolidin-2-one (less polar isomer), obtained as described in Preparation 76, 12 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) and 10 ml of anhydrous tetrahydrofuran were used, to give 1.20 g of the title compound, melting at 80° C. to 88° C., from the less polar diastereomer.
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].O=[O+][O-].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.CO>[C:20]1([CH2:19][N:26]2[CH2:6][CH:1]3[O:7][CH:4]([CH2:3][CH:2]3[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:5]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CC2C=CC1O2
Reactant: NCc1ccccc1
Agent: O=[O+][O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC2CN(Cc3ccccc3)CC1O2
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution 1,1-dimethylethyl 7-oxabicyclo[2.2.1]hept-5-en-2-ylcarbamate (1.0 g, 4.74 mmol) in MeOH/DCM (48 mL, 1:1) at −78° C. was bubbled through O3 until the solution maintained a blue color. N2 was then bubbled through until the blue color dissipated and a solution of benzylamine (0.49 mL, 4.5 mmol) and NaBH3CN (1.19 g, 19.0 mmol) in MeOH (22 mL) was added dropwise. After gradually warming to 25° C. over 12 hr, the mixture was partitioned between 6N NaOH and DCM. The aqueous layer was back-extracted several times with DCM and the combined organic fractions were concentrated and purified by column chromatography (silica, 0-1% MeOH in DCM (1% NH4OH )) affording the title compound as a clear oil (560 mg, 37%): LC/MS (ES) m/e 319 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.C1COCC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[NH:37][N:36]=[N:35][N:19]=3)[CH:16]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:28])[F:26])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(-c2nnn[nH]2)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile (76 mg, 0.17 mmol) in 2 mL of toluene was added trimethyltin azide (41 mg, 0.20 mmol). The reaction mixture was heated to 105° C. and stirred overnight TLC showed starting material to still be present so additional trimethyltin azide (41 mg, 0.20 mmol) was added. The reaction mixture was stirred overnight at 105° C., cooled to room temperature, then THF (800 μL) and concentrated HCl (500 μL) were added. HPLC analysis showed 2 peaks after 5 hours, so additional concentrated HCl (200 μL) was added. After stirring overnight, HPLC analysis showed the reaction to be complete. The mixture was filtered through a celite plug and evaporated in vacuo. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 27.2 mg (33%) of the desired tetrazole product as an oil. HRMS calcd. for C19H16F7N5O2: 480.1270 [M+H]+, found: 480.1252. 1H NMR (CDCl3) δ 3.66-3.99 (m, 2H), 4.45-4.75 (m, 3H), 5.80 (dt, 1H), 6.49-6.70 (m, 1H), 6.95 (s, 1H), 6.97-7.06 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].O[C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.ClCCl>[CH:49]([C:48]1[CH:51]=[CH:52][C:45]([O:42][C:41](=[O:43])[CH:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:37][CH:38]([CH3:39])[CH3:40])=[CH:46][CH:47]=1)=[O:50]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=Cc1ccc(O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C=O)cc1

Procedure:
BOP (13.0 mmol) was added to a solution of N-tert-butyloxycarbonyl-L-leucine (10.9 mmol) and 4-hydroxybenzaldehyde (13.0 mmol) in dry DMF (12 mL), and stirred to dissolve. N,N-Diisopropylethylamine (43.0 mmol) and 4-dimethylaminopyridine (1 mmol) were added with stirring. The resulting solution was stirred for 2.5 hours. The reaction mixture was covered with dichloromethane (100 mL) and washed with water, saturated aqueous sodium bicarbonate, and saturated brine. The dichloromethane was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting red oil was purified by column chromatography on silica gel with dichloromethane as an eluant.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:31]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH:32]4[CH2:33][CH2:34][CH2:35][N:30]([CH3:29])[CH2:31]4)[CH2:42][CH2:41]3)=[O:26])[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Reactant: CN1CCCC(CN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2noc(C(=O)N3CCN(CC4CCCN(C)C4)CC3)n2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.07 mmol), 1-[(1-methylpiperidin-3-yl)methyl]piperazine (31 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using prep method C, then FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]([OH:25])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:30]1([NH:32][C:23]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:31][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 174.5 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-phenyl-1H-1,2,3-triazole-4-carboxylic acid (203 mg, 0.604 mmol) obtained in Example 105a), HOBt (41.2 mg, 0.302 mmol, 0.5 eq.) and cyclopropylamine (0.056 ml, 0.785 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 3.0 ml), WSC (142 mg, 0.724 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 14 hr. Water (5 ml) was added to the reaction mixture and the mixture was stirred at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (198 mg, 0.527 mmol, 87.3%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5](Cl)=[N:4][CH:3]=1.CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.CO[CH2:28][CH2:29][O:30][CH2:31][CH2:32]OC>CCOC(C)=O>[Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([N:19]2[CH2:20][CH2:22][C:31]3([C:32]4[CH:3]=[CH:2][CH:7]=[CH:6][C:28]=4[CH2:29][O:30]3)[CH2:25][CH2:23]2)=[N:4][CH:3]=1
Reactant: Fc1ccc2[nH]c3c(Br)cnc(Cl)c3c2c1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCOCCOC
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]c3c(Br)cnc(N4CCC5(CC4)OCc4ccccc45)c3c2c1
Temperature: 150 °C

Procedure:
4-Bromo-1-chloro-8-fluoro-5H-pyrido[4,3-b]indole (150 mg, 0.501 mmol) and 3H-spiro[2-benzofuran-1,4′-piperidinium]chloride (565 mg, 2.504 mmol) were placed in a vial and suspended in diglyme (3 mL) and Hunig's Base (0.875 mL, 5.01 mmol). The reaction mixture was heated to 150° C. for 4 days. The solution was cooled to ambient temperature, diluted with EtOAc and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified on silica gel (EtOAc/hexanes gradient elution).
Reaction SMILES: [K].[S:2]([C:6]1[C:7]([C:11]([OH:13])=O)=[CH:8][S:9][CH:10]=1)(O)(=[O:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:15].[ClH:20]>O=P(Cl)(Cl)Cl>[Cl:20][S:2]([C:6]1[C:7]([C:11]([Cl:15])=[O:13])=[CH:8][S:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cscc1S(=O)(=O)O
Reactant: Cl
Agent: [K]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cl)c1cscc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
94.6 g (0.384 mole) of the monopotassium salt of 4-sulfothiophene-3-carboxylic acid (V) is suspended in 390 ml of POCl3 ; while stirring, 160.8 g (0.768 mole) of PCl5 is added (accompanied by vigorous evolution of HCl). The mixture is then heated for 3 hours on a water bath while stirring and then cooled to room temperature, inorganic salts are filtered off and the POCl3 is distilled off, as far as possible, at subatmospheric pressure. The residue is dissolved in 400 ml of dry chloroform to remove any inorganic salts which may still be present, filtered and evaporated. The residue crystallizes upon cooling and may be used in the next stage without further purification; melting point: 78° to 79° C.; yield: 90.8 g (96.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].C(OCC)(=O)C.O.[H+].[B-](F)(F)(F)[F:24]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([F:24])[CH:8]=1
Reactant: Cc1cc(Br)cc(N)c1C
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(F)c1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In 50 ml of 42% borofluoric acid was suspended 5.00 g of 5-bromo-2,3-dimethylaniline, followed by adding dropwise thereto 3.9 ml of an aqueous solution of 1.80 g of sodium nitrite under ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. The crystals precipitated were collected by filtration, dried under reduced pressure, and then heated at 60° C. on an oil bath. At the time when a theoretical amount of nitrogen was produced, the reaction mixture was cooled to room temperature and then added to a mixed solvent of 50 ml of ethyl acetate and 50 ml of water, and the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=30:1) to obtain 2.90 g of 5-bromo-2,3-dimethylfluorobenzene as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=2[CH3:35])=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([N:47]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:42][CH:41]=[CH:40]2.O.[C:63]([OH:67])(=[O:66])[CH:64]=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:64]([NH:36][C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[C:43]([N:47]([C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[N:42][CH:41]=[CH:40]4)[C:63]([OH:67])=[O:66])=[CH:28][C:27]=2[CH3:35])=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc([C@@H](C)NC(=O)OCc2ccccc2)c1
Solvent: O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc([C@@H](C)NC(=O)OCc2ccccc2)c1
Yield: 95 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 64D (175 mg, 0.37 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 65A (300 mg, 95%) as an oil. MS (ESI) m/z 848.5 (M+H)+.