Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(=[O:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][CH2:2][C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:3]
Reactant: CI
Reactant: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40.0 g of 2-acetylamino-3-(o-chlorobenzoyl)-4-methylthiophene in 800 ml of dimethylformamide is added 7.74 g of 63 % sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 61.34 g of methyl iodide in 184 ml of dimethylformamide is added thereto. The mixture is stirred at room temperature for 2 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give 2-(N-methylacetylamino)-3-(o-chlorobenzoyl)-4-methylthiophene as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[N:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH:1]1[CH:5]=[C:4]([CH:6]=[N:14][S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])[N:3]=[N:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1c[nH]nn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=Cc1c[nH]nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
1H-1,2,3-triazole-4-carbaldehyde (1 g, 10.3 mmol) and 2-methylpropane-2-sulfinamide (1.25 g, 10.3 mmol) were dissolved in tetrahydrofuran (20 mL). Titanium tetraisopropoxide (3.1 mL, 10.5 mmol) was added and the reaction heated at reflux for 8 hours. After cooling to room temperature, the reaction was quenched by adding saturated aqueous sodium chloride solution (5 mL) followed by dilution with tetrahydrofuran (80 mL) and stirred for 30 minutes. The mixture was filtered through a pad of Arbocel and the filtrate concentrated in vacuo, azeotroping with THF to afford the title compound (2.02 g, 98%).
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][C@@H:25]([CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[C:26]([O-:28])=[O:27].[Na+].[Na+].OC1C=CC(NC(=O)C)=CC=1.C(Cl)(=O)OC1C=CC([N+]([O-])=O)=CC=1>C(#N)C.O>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][C@@H:25]([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:26]([OH:28])=[O:27])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: N[C@@H](CS(=O)(=O)[O-])C(=O)[O-]
Agent: CC(=O)Nc1ccc(O)cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)N[C@@H](CS(=O)(=O)O)C(=O)O)cc1
Yield: 43 %

Procedure:
(2R)-2-[(4-Acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a) was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl Carbonate (3). A solution of 500 mg (2.35 mmol) of disodium (2R)-2-amino-3-sulfonato-propanoate (9) in approximately one (1) mL of water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (844 mg, 2.67 mmol) dissolved in 5 mL of acetonitrile (MeCN). The mixture was heated to about 55° C. for two (2) hours. After work-up procedures, the aqueous layer was lyophilized off to afford 400 mg (43% yield) of the crude 2-[(4-acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a). The material thus obtained was contaminated with some sodium chloride (NaCl) and other sodium salts. The crude product was further purified by preparative HPLC using a gradient consisting of acetonitrile and water containing 0.1 vol-% of formic acid. Samples eluting at 2% acetonitrile and 98% water were collected, frozen, and lyophilized off to afford 83 mg (9% yield) the target compound (13a) as a colorless solid. Rt=3.10 min. 1H NMR (300 MHz, D2O): δ=7.25 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 4.54-4.50 (m, 1H), 3.32-3.27 (m, 2H), 1.98 (s, 3H). LC/MS (ESI): m/z=347.0 [M+H]+, 714.8 [2M+Na]+.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (51 mg, 0.13 mmol), 3-methyltetrahydro-4H-pyran-4-one (46 mg, 0.4 mmol) and triethylamine (0.037 mL, 0.27 mmol) in dry methylene chloride (5 mL) was treated with sodium triacetoxyborohydride (85 mg, 0.40 mmol) at room temperature under N2 overnight. The reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (90 mg) was passed through a short silica gel pad (30:70 MeOH/EtOAc). The filtrate was concentrated and separated by chiral HPLC to give two isomers: first isomer; second isomer: MS calculated for C26H36F3N3O2: (M+H) 480; found 480.1 for both isomers.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=C(Br)Br)CC2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#C[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCCCC)CC2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 2.66 g of trans-1-(2,2-dibromovinyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane in 120 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 10 minutes with 15.2 ml of a 0.1N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -78° C. for a further 2 hours, then poured into 100 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (1.90 g) on silica gel with hexane gave 1.48 g (88%) of trans-1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane as a trans/cis epimer mixture (about 9:1). Fractional crystallization from 50 ml of methanol yielded 883 mg of pure trans-1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane as colourless crystals; m.p. (C-N) 51.3° C., cl.p. (N-I) 68.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C([Li])CCC.[N+:17]([CH:20]=[C:21]1[CH2:24][O:23][CH2:22]1)([O-:19])=[O:18].[Cl-].[NH4+]>C1COCC1.O>[N+:17]([CH2:20][C:21]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[CH2:24][O:23][CH2:22]1)([O-:19])=[O:18]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: O=[N+]([O-])C=C1COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC1(c2cccc(C(F)(F)F)c2)COC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 103 mg of 1-bromo-3-(trifluoromethyl)benzene (0.46 mmol) in 4 ml anhydrous THF is treated slowly at −78° C. with an n-butyllithium solution (1.6 M in hexane, 312 μl, 0.50 mmol). After 15 mins' stirring at −78° C., a solution of 50 mg (0.43 mmol) of 3-nitromethylenoxetane [Herstellung: G. Wuitschik et al., Agnew. Chem. Int. Ed. 45 (46), 7736-7739 (2006)] in 2 ml THF is added. The mixture is stirred overnight at −78° C. and then the reaction is stopped by addition of 5 ml of saturated ammonium chloride solution at −78° C. After warming to RT, the mixture is diluted with water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The oily residue is briefly dried under high vacuum. 53 mg (33% of theory) of the title compound in ca. 70% purity are obtained.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:27])[CH:22]4[CH2:26][CH2:25][NH:24][CH2:23]4)=[N:18][C:17]3=[O:28])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([NH2:49])=[O:48]>CN(C=O)C>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:27])[C@@H:22]4[CH2:26][CH2:25][N:24]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:23]4)=[N:18][C:17]3=[O:28])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NC(=O)CBr
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)[C@@H]1CCN(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-pyrrolidin-3-yl-amino)-thiazol-4-one (100 mg, 0.18 mmol) in DMF (2 mL) was added potassium carbonate (74 mg, 0.54 mmol) followed by 2-Bromo-acetamide (30 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (82 mg, 75%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CS(C)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
60% Sodium hydride (0.92 g) was dispersed in THF (30 ml). To the obtained suspension was added dropwise a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.80 g) in THF (10 ml) at 40-50° C. The mixture was stirred at the same temperature for 30 min, and a solution of 3-dimethylaminopropyl chloride (3.2 g) in toluene (20 ml) was added dropwise, which was followed by stirring for 10 min. Then, dimethyl sulfoxide (30 ml) was further added dropwise and the mixture was stirred at 65-70° C. for 3 hr. The reaction mixture was poured into ice water (200 ml) and extracted 3 times with toluene (60 ml). The organic layer was extracted twice with 20% aqueous acetic acid (60 ml). The aqueous layer was neutralized, extracted twice with toluene (60 ml) and washed with water. Anhydrous potassium carbonate (2 g) and silica gel (2 g) were added and the mixture was stirred and filtered. The solvent was evaporated to give 1-(3′-dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (3.37 g, 51.6%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1.Cl.[NH2:36][OH:37]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:36][OH:37])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:33])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:5][CH:4]=1
Reactant: O=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 15 g (0.033 mole) of 4'-fluoro-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride and 15 g of hydroxylamine hydrochloride in 120 ml of pyridine is stirred on a steam bath for about 4 hours then cooled to room temperature. The pyridine is removed at reduced pressure on a steam bath, and the residue is triturated with a dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate, filtered and concentrated to a residue which is triturated with hexane. The resulting solid is filtered off and recrystallized from ethanol to give 4'-fluoro-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone oxime.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[NH:1][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Product: Clc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
A mixture of 23.2 g (0.10 mole) of 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mole) of 3-amino-2-chloropyridine (96%) were heated for 1.5 hr at 180° C. under nitrogen atmosphere. The mixture was cooled to room temperature and methylene chloride added. After stirring for 30 min., solids were separated by filtration and triturated in hot 190 proof ethanol. The remaining insoluble material was collected by filtration and recrystallized from benzene-isooctane to give 2.7 g product, m.p. 203°-204.5° C. Drying conditions prior to analyses were: overnight at 97°-98° C./0.1 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[NH:8][C:9]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:21])[CH3:20])=[O:12])=[N:10][C:6]=2[CH:5]=1)([O-])=O.CN(C)C1C=CC(OC)=CC=1S(C1NC2C=CC(C(OC)=O)=CC=2N=1)=O>C(O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]2[NH:8][C:9]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:20])[CH3:21])=[O:12])=[N:10][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccccc1S(=O)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=[Pt]=O
Agent: COC(=O)c1ccc2[nH]c(S(=O)c3cc(OC)ccc3N(C)C)nc2c1
Solvent: CCO
Product: CN(C)c1ccccc1S(=O)c1nc2cc(N)ccc2[nH]1
Reaction time: 72 h

Procedure:
2-(5-Nitro-1H-benzimidazol-2-yl sulphinyl)-N,N-dimethylbenzenamine (the product of Example 2 (c) (3g) was suspended in ethanol (300 ml), and hydrogenated at 1 atmosphere at room temperature, using platinium oxide as catalyst, for 3 days.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].CCCCC=CCCC>C(O)(C)C>[N+:8]([CH2:11][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)([O-:10])=[O:9]
Reactant: O=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC=CCCCC
Solvent: CC(C)O
Product: O=C1CCCC(C[N+](=O)[O-])C1
Yield: 100 %

Procedure:
21.9 g of cyclohexanone are left to stand together with 175 ml of nitromethane and 2.1 g of 5-diazabicyclo[4.3.0.]non-5-ene (DBN) in 250 ml of isopropanol at room temperature for 2 days. The working up is carried out in analogy to the procedure for Example 1 and provides 37.2 g (100% of theory) of 3-(nitromethyl)cyclohexanone which is pure enough for the next reaction. Rf =0.62 CH2Cl2 :CH3OH=99:1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>[Cu].C1(C)C=CC=CC=1>[O:15]([C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1cccc(Oc2ccccc2)c1
Temperature: 210 °C
Yield: 36.8 %

Procedure:
A mixture of 1,3-dibromobenzene (15.7 g), phenol (8.0 g), potassium hydroxide (3.8 g, mortar-ground) and copper powder (0.1 g) was heated at reflux for 18 hours at 210° C. After cooling, the reaction mixture was mixed with toluene and successively washed with 10% aqueous sodium hydroxide and water. The toluene was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane), thereby giving 6.1 g of the desired compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[N:11][C:12]=1[F:13].C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>CCCCCC.C1COCC1>[F:13][C:12]1[N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:9]=[CH:8][C:7]=1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCCOc1ccc(Br)c(F)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
A solution of n-butyllithium (0.693 g, 10.83 mmol) in n-hexane (4.33 mL) was added to a stirred mixture of 3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2 g, 7.22 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.014 g, 10.83 mmol) in THF (20 mL) at −78° C. over a period of 20 minutes under an inert atmosphere. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was quenched with sat. NaHCO3 solution and concentrated in vacuo. The crude product was purified by FCC, elution gradient 0 to 10% MeOH in DCM, to afford the desired material (2.50 g, 1.07%). Mass Spectrum: m/z (ES+)[M+H]+=325.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:25]([O:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH2:1])=[CH:13][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A slurry containing of the product from Example 85A (0.2 g, 0.763 mmole) and cesium carbonate (0.25 g, 0.763 mmole) in dimethylformamide (5 ml) was treated with benzyl bromide (0.091 ml, 0.763 mmole) and the resulting slurry was stirred 18 hours at room temperature. Afterwards ice water (50 mL) was added to the solution and to the resultant slurry was added ethyl acetate (50 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a yellow solid as the title compound (0.24 g, 89%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH:16]=O)=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:11]2[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:23]1[CH3:32]
Reactant: O=Cc1ncccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ncccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 3-benzenesulfonylpyridine-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)=[C:4]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:25]([S:22]([C:4]1[CH:3]=[C:2]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:20]([CH3:21])[C:11]2=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]2[N:9]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CCS(=O)(=O)c1cc(Br)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCS(=O)(=O)c1cc(-c2ncccn2)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A mixture of 2-(4-bromo-2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.20 g), 2-tributylstannylpyrimidine (0.17 g), tetrakis(triphenylphosphine)palladium (27 mg) and toluene (5 ml) was heated at reflux under nitrogen atmosphere for 5.5 hours. After the mixture was cooled to room temperature, to the mixture, 2-tributylstannylpyrimidine (0.17 g) and tetrakis(triphenylphosphine)palladium (27 mg) were added, and stirred under reflux for further 8 hours. After the mixture was cooled to room temperature, water was poured thereinto, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.20 g of 2-[2-ethylsulfonyl-4-(pyrimidine-2-yl)-phenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 333).
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[NH2:2].[OH-].[Na+].[Na].Cl>C(O)C.O>[C:1]([C:4]1[C:5]2[N:6]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cn2c(n1)c(C(N)=O)nc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC(=O)c1nc2ccccc2n2cc(C(=O)O)nc12
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A suspension of 0.315 g of the product of Step B, 35 ml of water, 12 ml of ethanol and 6 ml of 1 N sodium hydroxide was stirred overnight to obtain a suspension of the white sodium salt which was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 0.28 g of 4-carbamoyl-imidazo-[1,2-a]-quinoxaline-2-carboxylic acid in the form of a buff crystalline solid melting at 298°-300° C.