Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[N:9])=[CH:6][N:7]=1.[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([NH:30][C:31](=[O:34])[CH2:32][SH:33])[CH:24]=1)=[O:21])([CH3:16])[CH3:15])#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:11][C:10]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([C:8]#[N:9])[N:4]=2)[S:33][C:32]=1[C:31]([NH:30][C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:35]=[CH:36][CH:37]=[C:17]([C:14]([C:12]#[N:13])([CH3:15])[CH3:16])[CH:18]=2)[CH:28]=[CH:27][C:26]=1[CH3:29])=[O:34]
Reactant: N#Cc1cnc(Br)c(C#N)n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2ncc(C#N)nc2c1N
Yield: 14.8 %

Procedure:
A solution of 3-bromopyrazine-2,6-dicarbonitrile 52 (17.06 mg, 0.082 mmol), 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (0.082 mmol, 30 mg) and potassium carbonate (13.54 mg, 0.098 mmol) in ethanol (1 mL) was stirred at 40° C. for 1 h. Quenched in 2N HCl solution and extracted with CH2Cl2. Organic layer was washed with brine, dried and evaporated. Purification by chromatography (5-10% EtOAc in CH2Cl2) gave the title compound 7-amino-2-cyano-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 53 (6 mg, 14.83%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.22 (s, 3H), 7.29 (m, 2H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (m, 1H), 7.81 (d, 2.0 Hz, 1H), 7.94 (d, J=Hz, J=7.8 Hz, 1H), 8.05 (t, J=2.0 Hz, 1H), 9.65 (s, 1H), 10.34 (s, 1H). (m/z)=496 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1.[OH-].[Na+].Cl[CH:18]([F:20])[F:19]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:18]([F:20])[F:19])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(Cl)ccc1-c1cc(OC(F)F)[nH]n1
Reaction time: 6 h
Yield: 14.7 %

Procedure:
64 g of the 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole obtained in step 1.1 were initially charged in 600 ml of dioxane. A solution of 24 g of sodium hydroxide in 70 ml of water was added, and the mixture was heated at reflux. With stirring, 238.7 g (2.76 mol, 9.2 eq.) of gaseous chlorodifluoromethane were added, and during the addition the pH was monitored constantly and, when it approached the neutral range (pH<9), increased by addition of additional NaOH solution to about pH 12. After 6 h, the mixture was allowed to cool, 1800 ml of water were added and the mixture was extracted twice with in each case 500 ml of MTBE. The combined organic phases were washed with in each case 500 ml of water and saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. This gave 58.7 g of crude 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole. 32.3 g of this mixture were distilled under reduced pressure, giving 11.6 g of the title compound as an oil of a purity of 86%. Yield: 22.9%
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH2:31])[C:14]1=[O:32])=[O:11])[CH2:2]2.[F:33][C:34]([F:55])([F:54])[C:35]1[CH:36]=[C:37]([NH:41][C:42](=O)[O:43]C2C=CC([N+]([O-])=O)=CC=2)[CH:38]=[CH:39][CH:40]=1.C(N(CC)CC)C.O>CN(C)C=O.C(OC(C)C)(C)C>[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:42]([NH:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:54])[F:55])[CH:36]=3)=[O:43])[C:14]1=[O:32])=[O:11])[CH2:4]2
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of (3RS)-1-{(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl}-3-amino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (100mg) and 4-nitrophenyl N-(3-trifluoromethylphenyl)carbamate (90.1 mg) in dimethylformamide (2 ml) was added triethylamine (28 mg) under stirring at ambient temperature. The mixture was stirred for 3.5 hours under the same condition. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water three times and dried over magnesium sulfate. The solvent was removed in vacuo to give an amorphous mass, which was pulverized in diisopropyl ether under vigorous stirring. The resulting powder was collected by filtration and washed with diisopropyl ether to afford N-[(3RS)-1-{(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl}-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-trifluoromethylphenyl)urea (124.4 mg).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:8]2)=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[N:8]2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(-n2nc(-c3ccc([N+](=O)[O-])cc3)cc2N)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(-c3ccc(N)cc3)cc2N)cc1

Procedure:
To a solution of 1-(4-tolyl)-3-(4-nitrophenyl)-5-aminopyrazole (0.48 g, 1.6 mmol) in EtOAc (50 mL) at room temperature was added 10% Pd-C (0.1 g). The mixture was treated with hydrogen gas at 30 psi for 30 min. on a Parr shaker. The mixture was filtered through Celite and the solvent removed by rotary evaporation to yield 1-(4-tolyl)-3-(4-aminophenyl)-5-aminopyrazole as an oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][O:8][CH2:7][N:6]1[C:10](=[O:15])[C:11]([O:13]C)=O)=[O:4].[CH3:16][C:17]([Mg]Cl)([CH3:20])[CH2:18][CH3:19]>C1COCC1>[CH3:16][C:17]([CH3:20])([CH2:18][CH3:19])[C:11](=[O:13])[C:10]([N:6]1[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:9][O:8][CH2:7]1)=[O:15]
Reactant: CCC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)N1COCC1C(=O)OC
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)N1COCC1C(=O)OC
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of methyl 2-[4-(methoxycarbonyl)(1,3-oxazolidin-3-yl)]-2-oxoacetate (2) (0.84 g, 3.87 mM) in THF (50 ml) cooled to −78° C. was added 1,1-dimethylpropylmagnesium chloride (1M in THF, 8 ml, 8 mM). After 3 hrs. at −78° C. the mixture was quenched with saturated NH4Cl (50 ml) and extracted with ethyl acetate (100 ml). The organic layer separated, washed with brine (100 ml), dried with anhydrous magnesium sulfate, filtered and evaporated. The resulting pale yellow oil was flash chromatographed eluting with 20% EtOAc/hexane. A clear oil (3) (0.61 g, 61%) was obtained.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.Cl.[NH2:39][CH:40]1[C:61](=[O:62])[N:42]2[C:43]([C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=3)=[O:49])=[C:44]([Cl:47])[CH2:45][S:46][C@H:41]12>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])=[C:44]([Cl:47])[CH2:45][S:46][C@H:41]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 89.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.03 g.), trimethylsilylacetamide (5.9 g.), 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (2.3 g.) and ethyl acetate (60 ml.) were treated in a similar manner to that of Example 11-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 3.55 g.)
Reaction SMILES: [CH3:1][C:2]([S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.S(Cl)(Cl)=O.CN(C=O)C.CCN(C(C)C)C(C)C.[NH2:35][C:36]1[O:40][N:39]=[C:38]([C:41]([CH3:45])([CH3:44])[C:42]#[N:43])[CH:37]=1>C1(C)C=CC=CC=1>[C:42]([C:41]([CH3:45])([CH3:44])[C:38]1[CH:37]=[C:36]([NH:35][C:3](=[O:5])[C:2]([CH3:1])([S:7]([CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:9])=[O:8])[CH3:6])[O:40][N:39]=1)#[N:43]
Reactant: CC(C)(C(=O)O)S(=O)(=O)CCCC(F)(F)F
Reactant: CC(C)(C#N)c1cc(N)on1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C#N)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCCC(F)(F)F)on1
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To 100 mg (0.38 mmol) of 2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid (intermediate 5) in toluene (4.07 mL) are added 55.3 μL (0.76 mmol) thionyl chloride and 3.10 μL (0.04 mmol) DMF. The solution is stirred at reflux for 1 h. In a second flask 78.7 μL (0.46 mmol) DIPEA are added to 63.4 mg (0.42 mmol) of 2-(5-amino-isoxazol-3-yl)-2-methyl-propionitrile (intermediate 7) in toluene (2.03 mL). The mixture is stirred at RT for 5 min, then added to the acid chloride and stirring is continued at RT for 16 h. The reaction mixture is purified by HPLC-MS to afford 78.7 mg of N-[3-(cyano-dimethyl-methyl)-isoxazol-5-yl]-2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionamide. Yield: 52%; ESI-MS: 396 [M+H]+; HPLC (Rt): 1.14 min (method G); 1H-NMR (400 MHz, DMSO-d6): 1.68 (s, 6H), 1.70 (s, 6H), 1.86-1.91 (m, 2H), 2.47-2.52 (m, 2H), 3.34-3.40 (m, 2H), 6.57 (s, 1H), 11.64 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].C1COCC1.Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C([O-])(O)=O.[Na+]>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.25 mL 2-methoxyethanol (3.17 mmol) are added to a mixture of 80 mg (3.17 mmol) sodium hydride and 5 mL THF. The mixture is stirred at rt for 10 min. Subsequently, 500 mg (2.11 mmol) 2,5-dibromopyridine are added and the mixture is stirred for 5 h at 75° C. After that time, the reaction mixture is diluted with sat. aq. NaHCO3 solution and extracted with EtOAc. The organic layer is dried over magnesium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 85/15).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of known 6-nitro-1H-indole (5 g, 31 mm) in dimethylformamide (DMF) (50 mL) was cooled to 0° C. and treated with NaH (1 g, 37m). After stirring at 0° C. for two hours, CH3I (2.3 mL, 37 mm) was added, and the reaction was stirred overnight while allowing to warm to room temperature. After pouring into H2O (500 mL), the mixture was extracted with ethyl acetate (EtOAc) (200 mL×4). The combined organic fractions were dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded the 1-methyl-6-nitro-1H-indole (5.34 g, 97%).
Reaction SMILES: Br[C:2]([F:17])([F:16])[O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15].[Sb](F)(F)[F:19]>C(OCC)C.[Sb](Cl)(Cl)(Cl)(Cl)Cl>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[O:3][C:2]([F:17])([F:19])[F:16])[C:8]([O:10][CH3:11])=[O:9]
Reactant: F[Sb](F)F
Reactant: COC(=O)c1ccc(OC(F)(F)Br)c(OC)c1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(OC(F)(F)F)c(OC)c1
Temperature: 170 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
Antimony (V) Chloride (26.4 mg, 0.088 mmol) was added to a stirred, room temperature mixture of 173A (550 mg, 1.768 mmol) and antimony trifluoride (221 mg, 1.238 mmol) in a sealed tube, and the mixture was stirred at 170° C. for 4 h. The mixture was cooled, diluted with diethyl ether (50 mL), washed with water (50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel; 24 g prepacked column, eluting with EtOAc/isohexane=10% to give methyl 3-methoxy-4-(trifluoromethoxy)benzoate 173B (240 mg, 0.959 mmol, 54.3% yield) as a white solid.
Reaction SMILES: [N+]([O-])(O)=O.S(=O)(=O)(O)O.[CH3:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([CH3:21])([CH2:14]3)[CH2:12]1)[CH2:18]2.[CH:22]([NH2:24])=[O:23]>O.ClCCl>[CH:22]([NH:24][C:15]12[CH2:20][C:11]3([CH3:10])[CH2:18][CH:17]([CH2:19][C:13]([CH3:21])([CH2:12]3)[CH2:14]1)[CH2:16]2)=[O:23]
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Reactant: NC=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC12CC3CC(C)(C1)CC(NC=O)(C3)C2
Temperature: 0 °C
Yield: 89.3 %

Procedure:
In sequence, 4 mL 65% technical nitric acid and then within three hours 50 mL 98% technical sulfuric acid are added to 6.572 g (40 mmol) 1,3-dimethyladamantane at 0° C. It is stirred over night at 0° C. and the mixture is poured at 0° C. onto 100 mL formamide in a round bottom flask which is provided with a drying tube. This mixture is stirred for 30 min at 0° C. and for 90 min at room temperature and 200 mL dichloromethane and 200 mL water are added. After phase separation, the organic phase is washed with water and 2% NaHCO3-solution, is dried, over Na2SO4 and is freed from solvents at the rotary evaporator. The remaining oil is chromatographically purified (SiO2, CHCl3/acetone (20:1), Rf=0.39). 7.41 g (89.3%) of the formamide are obtained as a nearly colourless solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:15][CH2:16][CH3:17])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH2:15]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14])[CH2:16][CH3:17]
Reactant: CCCc1ccc(N)cc1O
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: CCCc1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (1.26 mL, 14.0 mmol), 5-amino-2-propylphenol (1.1 g, 7.0 mmol) and 37% HCl solution (1.21 mL, 14.0 mmol) in 10%, aqueous EtOH solution (20 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 36% yield (588 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:14][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:1]3([CH3:2])[O:20][CH2:19][CH2:18][O:3]3)=[CH:13][CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:8][C:9]1=[O:15]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN1C(=O)CC(C)(C)c2cc(C3(C)OCCO3)ccc21
Yield: 94.1 %

Procedure:
5.0 g of 6-acetyl-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 200 ml of benzene and, after the addition of 2.1 g of ethylene glycol and a few crystals of p-toluenesulphonic acid, the mixture was boiled under a water separator for 5 hours. After cooling, the mixture was diluted with ethyl acetate, washed with dilute sodium hydrogen carbonate solution, dried and evaporated. There were obtained 5.6 g of 3,4-dihydro-1,4,4-trimethyl-6-(2-methyl-1,3-dioxolan-2-yl)-2(1H)-quinolinone in the form of a colourless oil which solidified upon standing in a refrigerator; melting point 81°-83° C. This compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=3[CH3:21])=[CH:7][C:5]=2[N:6]=1.[H][H]>C(O)C.[Pd]>[CH3:21][C:13]1[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1nc2cc(Oc3ccc([N+](=O)[O-])cc3C)ccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2cc(Oc3ccc(N)cc3C)ccc2o1
Yield: 68.5 %

Procedure:
To a solution of 2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole (671 mg, 2.36 mmol) in ethanol (10 mL) was added 10% palladium on carbon (50 mg, 0.047 mmol). The reaction mixture was subjected to 40 psi of hydrogen for 2.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed to provide the product (0.411 g, 69%) as yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[C:7]([CH:6]([Br:15])[C:4]([O:3][CH2:2][CH3:1])=[O:5])(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
25 ml (0.144 mol) of ethyl benzoyl acetate are dissolved in 50 ml of CCl4, 8.5 ml of bromine are added dropwise at 5° C. and the brown solution is stirred at 5° C. for 1 h, at room temperature for 3 h and at 60° C. for 2 h. It is concentrated to dryness, the residue is taken up in EA, the EA solution is washed with 10% strength Na2SO3 solution and satd. NaCl solution, dried over MgSO4 and concentrated, and the residue is dried in a high vacuum. 38 g of the title compound result as a red oil.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH3:21][C:22]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:21][C:22]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][CH2:1][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Product: Cc1c(NCc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 76A and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]#[C:3][CH3:4].[CH2:8]([SH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C1CCN2C(=NCCC2)CC1.CCOCC>[CH2:8]([S:16]/[C:3](/[CH3:4])=[CH:2]/[C:1]([O:6][CH3:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCS
Reactant: CC#CC(=O)OC
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCS/C(C)=C/C(=O)OC
Reaction time: 8 h

Procedure:
Two drops of DBU is added to methyl 2-butynoate (6.0 g) under N2. 1-Octanethiol (8.96 g, 61.2 mmol) is added dropwise over 20 min. with cooling with an ice bath. The mixture is allowed to come to RT and is stirred overnight. It is then diluted with ether, washed, dried and stripped and the product is purified by prep. TLC to give methyl (E)-3-octylthio-2butenoate.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:4]=2[CH:3]=1.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>[Cu]I>[N:21]1([C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:4]=3[CH:3]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: c1cn[nH]c1
Reactant: Brc1ccc2c3ccccc3n(C3CCCCO3)c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: c1ccc2c(c1)c1ccc(-n3cccn3)cc1n2C1CCCCO1
Temperature: 90 °C
Yield: 40 %

Procedure:
Under a nitrogen atmosphere, 10 mmol of 2-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole, 15 mmol of pyrazole, 1 mmol of copper(I)iodide, 25 mmol of potassium carbonate, and 2 mmol of L-proline were combined in 25 mL of stirring degassed dimethyl sulfoxide. The mixture was heated to 90° C. for 3 days before being cooled and separated between dichloromethane and water. The water layer was washed twice with dichloromethane and the organics were combined and washed once with brine. The organic fraction was dried with magnesium sulfate and concentrated under reduced pressure and subjected to column chromatography of silica with dichloromethane as the eluent. After concentrating under reduced pressure, 2-(1H-pyrazol-1-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole was isolated in a 40% yield.
Reaction SMILES: [N:1]1([CH:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[C:9]([CH2:19][O:20]C3CCCCO3)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[OH:20][CH2:19][C:9]1[CH:8]=[C:7]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:12]=[CH:11][C:10]=1[NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17]
Reactant: CCOC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1CO
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of 10.5 parts of intermediate 60, namely ethyl [4-[(1H-imidazol-1-yl)phenylmethyl]-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]carbamate, 5.5 parts of 4-methylbenzenesulfonic acid and 198 parts of ethanol was stirred over weekend at room temperature and for a short time at 50°-60° C. After cooling, there were added ethanol and Na2CO3. The whole was stirred for 15 min. and was then filtered. The filtrate was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane. The combined dichloromethane layers were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene. The crystallized product was filtered off, stirred in 2,2'-oxybispropane and dried in vacuo, yielding 4.65 parts (46.0%) of ethyl [2-(hydroxymethyl)-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]carbamate; mp. 143.1° C. (interm. 61).