Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C@H:6]([C:26](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:27])[C@@H:7]([C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[OH:8].[Li+].[OH-].OO.C(OCC)(=[O:51])C>C1COCC1.O>[F:44][C:42]1[CH:41]=[C:4]([CH:3]=[C:2]([F:1])[CH:43]=1)[CH2:5][C@@H:6]([C@@H:7]([C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[OH:8])[C:26]([OH:51])=[O:27]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-tert-butyl 3-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (4), 13.0 g, 21.5 mmol) in THF (500 mL) was added a solution of LiOH (1.03 g, 43 mmol) in H2O (100 mL), then 30% H2O2 (24.4 g) was added at 0° C. This reaction mixture was warmed up to rt over 1 h and stirred at rt for 4 h. Ethyl acetate (1000 mL) was added and washed with 1N HCl, and H2O, dried (Na2SO4), and concentrated in vacuo to give the crude product which was ready for next step without purification. MS (ESI) (M−H)− 446.07.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g) and N,N-dimethylformamide (80 ml) was stirred at room temperature for 20 hours and water (800 ml) was added. The resultant crystals were filtered and washed with water to obtain N-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (10.1 g, yield 90%) as pale-brown crystals. m.p. 146-147° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][NH2:14]>O.Cl.C(OCC)C>[N:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])=[N+:14]=[N-:1]
Reactant: NNc1ccccc1F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
Sodium nitrite (510 mg) dissolved in 2 ml of water was dropped, under cooling with ice, into a solution of 1.0 g of 2-fluorophenylhydrazine hydrochloride in 5 ml of concentrated hydrochloric acid and 6 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 2 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 400 mg of the title compound as a brown oily crude product.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[BrH:18].N([O-])=O.[Na+]>O>[Br:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To an ice-cooled mixture of 7-ADCA (10.0 g, 0.4667 mol), ethanol (270 ml), water (83 ml) and hydrobromic acid (48%, 56.7 ml), sodium nitrite (4.67 g, 0.6769 mol) was added in small portions over 25 minutes and the mixture was stirred for 2.5 hours at ice-temperature. Ethanol was removed under reduced pressure and the residual mass was diluted with methylene chloride, washed with water. The aqueous washings were saturated with brine and re-extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 9.8 g (75.5%) of 7α-bromo-3-methyl -3-cephem-4-carboxylic acid. This crude acid was directly used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].S([O-])([O-])(=O)=O.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][O:20][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(COC)nc21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)OC(C)(C)C)c(COC)nc21
Reaction time: 2 h
Yield: 68.1 %

Procedure:
[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (57 mg), toluene (0.3 ml), 50% aqueous NaOH solution and tetrabutylammonim sulfate (32 mg) were stirred at room temperature. tert-Butyl bromoacetate (53 mg) was added dropwise and stirring was continued for 2 hours. Water (3 ml) was added and organic layer was separated. Water layer was extracted with EtOAc (×2). Organic layer was combined and dried over MgSO4. The solvent was evaporated to give dark brown oil. The crude compound was purified by flash column chromatography on silica gel (CHCl3:MeOH=50:1) to give tert-butyl {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetate (53 mg) as colorless oil
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH2:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CO/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9]/[CH:22]=[C:23](\[C:30]([O:32][CH3:33])=[O:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27]
Reactant: CO/C=C(/C=C/C(=O)OC)C(=O)OC
Reactant: Nc1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/C(=C/Nc1c(Cl)cccc1Cl)C(=O)OC
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a solution of (2,6-dichlorophenyl)amine (12.8 g) in THF (73 mL) was added an 1 M THF solution of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (79.8 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To this solution was added a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (14.52 g) in THF (35 ml) at once, and the resulting mixture was stirred at 0° C. for 3 hr. The reaction mixture was diluted with EtOAc (150 mL) and washed with a mixture of 1 M HCl (200 mL) and brine (150 mL), saturated aqueous NaHCO3 (150 mL) and brine successively, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of EtOAc and hexane (1:2) and collected by filtration to give dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (9.28 g). The filtrate was evaporated in vacuo and the residue was purified by silica gel (200 g) column chromatography eluting with EtOAc-hexane (1:2) followed by triturating the isolated material with EtOAc-hexane (1:2) to afford dimethyl (2E,4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-pentenedioate (1.30 g).
Reaction SMILES: C(OC(N1CC[C@@H](NC2C=CC(N3C[C@H](CNC(=O)C)OC3=O)=CC=2F)C1)=O)(C)(C)C.C([O:34][C:35]([C@H:37]1[C@@H:41]([CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][N:39]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:38]1)=[O:36])C.O.[OH-].[Li+].O>C1COCC1>[CH2:51]([N:39]1[CH2:40][C@H:41]([CH2:42][NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[C@H:37]([C:35]([OH:36])=[O:34])[CH2:38]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Agent: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(F)c2)C(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2.9 (3R, 4R) and (3S, 4S)-1-benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylic acid ethyl ester (8.0 mmol) in 50 ml THF were added 671 mg lithium hydroxide mono hydrate (, 16 mmol) and 0.5 ml water. The solution was stirred at 40° C. and the reaction monitored by TLC. After 72 h the solvent was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture.
Reaction SMILES: C(=O)([O-])N.Cl[C:6]([O:8][CH3:9])=[O:7].[CH3:10][O:11][C:12]([C:14]1[S:33][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]=3[S:24][C:16]=2[C:15]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:13]>>[CH3:10][O:11][C:12]([C:14]1[S:33][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([N:25]([CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:6]([O:8][CH3:9])=[O:7])[C:23]=3[S:24][C:16]=2[C:15]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:13]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NCC3CCCCC3)cccc12
Reactant: COC(=O)Cl
Agent: NC(=O)[O-]
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N(CC3CCCCC3)C(=O)OC)cccc12
Yield: 63.7 %

Procedure:
Step B Carbamate Formation: Addition of methyl chloroformate (0.05 mL, 0.65 mmol) to 7-(Cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (60 mg, 0.13 mmol) was carried out following a procedure similar to that delineated in Step B, Example 27, affording 43 mg of 7-(Cyclohexylmethyl-methoxycarbonyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (63% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25][CH:24]2[CH2:27][NH:28][CH2:29][CH:23]12.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:28]2[CH2:27][CH:24]3[CH:23]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2CN(c3c(Br)cnc4[nH]cc(NC(=O)c5cccnc5)c34)CC21
Temperature: 140 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (180 mg, 0.537 mmol, Example 1, Step I), tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate hydrochloride (334 mg, 1.34 mmol), and DIEA (0.234 mL, 1.34 mmol) in n-BuOH (2 mL) was stirred at 140° C. for 5 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The residue obtained was purified by reverse phase HPLC (Gilson) to provide tert-butyl 5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo [3,4-b]pyrrole-1(2H)-carboxylate (50 mg, 18% yield).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([F:10])[CH2:7][C@H:6]1[C:11]#[N:12])=[O:4].Cl.F[C@@H]1CN[C@H](C(N)=O)C1.[Cl:23]CC(Cl)=O>>[Cl:23][CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([F:10])[CH2:7][C@H:6]1[C:11]#[N:12])=[O:4]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: NC(=O)[C@@H]1C[C@H](F)CN1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl

Procedure:
According to the production process of (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile described in WO 02/38541 pamphlet, (2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (5.00 g) and chloroacetyl chloride (2.60 mL) were used to obtain (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (4.96 g).
Reaction SMILES: C(N(C[N:7]1[CH2:12][CH2:11][CH2:10][C:9](=[C:13](O)[C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)C1=O)CC)C.[ClH:23]>CC(C)=O.C(O)(C)C>[ClH:23].[ClH:23].[CH3:20][C:18]1[CH:19]=[C:14]([C:13]2[CH2:9][CH2:10][CH2:11][CH2:12][N:7]=2)[CH:15]=[N:16][CH:17]=1
Reactant: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Cc1cncc(C2=NCCCC2)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (10 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25].[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:15]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[CH3:13])[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C2CC(=O)C=C(O)C2)c(C)c1

Procedure:
Diethyl malonate (10.1 g; 60 mmole) was added to a solution of sodium metal (1.4 g; 60 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(2,4,6-trimethylphenyl)but-1-en-3-one (11.4 g; 61 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (7.3 g; 180 mmole in 100 ml of water) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-mesitylcyclohex-2-en-1-one, was obtained as a pale yellow solid (10.9 g; 77.4%), mp 165° C. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.0-4.1 (14H, m); 5.2 (1H, s); 6.8 (2H, s); 11.2 (1H, br.s.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
A mixture of ethyl 7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.636 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture wax filtered and washed water (20 mL) and methanol (5 mL) to obtain a white solid, which after dried in vacuum at 50° C. afforded the title compound (34.6 mg, yield 15%). LC-MS (ESI) m/z: 362 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) 6 (ppm): 3.56 (s, 3H), 4.48-4.49 (d, J=6.0 Hz, 1H), 5.01-5.03 (m, 1H), 6.70-6.71 (m, 1H), 6.81-6.84 (m, 1H), 6.98-7.02 (m, 2H), 7.14-7.26 (m, 5H), 7.66-7.67 (m, 1H), 12.33 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:57][O:58][CH2:59][CH:60](O)[CH2:61][O:62][CH3:63]>O1CCCC1>[CH3:57][O:58][CH2:59][CH:60]([CH2:61][O:62][CH3:63])[O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Reactant: COCC(O)COC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)OC)[nH]c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (2.75 g), tributylphosphine (3.7 mL), 1,1′-(azodicarbonyl)dipiperidine (3.8 g), 1,3-dimethoxypropan-2-ol (1.8 g) and tetrahydrofuran (50 mL) was stirred at 50° C. for 8 h. Tributylphosphine (1.9 mL), 1,1′-(azodicarbonyl)dipiperidine (1.9 g) and 1,3-dimethoxypropan-2-ol (0.9 g) were added to the mixture again, and the mixture was stirred at 50° C. for 8 h. Furthermore, tributylphosphine (3.7 mL), 1,1′-(azodicarbonyl)dipiperidine (3.8 g) and 1,3-dimethoxypropan-2-ol (1.8 g) were added to the mixture. After stirring at 50° C. for 24 h, the mixture was cooled to 0° C. and a precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 80/20, volume ratio) twice, followed by basic silica gel column chromatography (ethyl acetate/hexane 20/80 to 85/15) to give the crude title compound (3.42 g) as a yellow oil. MS 465 (MH+).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9].C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.O>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[CH:13][CH:12]=1)[CH2:2]2.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9](=[O:22])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[N:20][N:19]=[N:18]4)=[CH:15][CH:16]=2)[CH2:4]3)=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (100 mg, 0.335 mmol) was combined with 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.34 mmol) and Hunig's base (43.3 mg, 0.335 mmol) in acetonitrile (1 mL) and stirred at 60° C. for 5 h. Purification by mass-directed HPLC afforded the title compound. LC/MS: [(M+1)]+=448.
Reaction SMILES: COC1C=CC=CC=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15]C(C)(C)C=C2CSCCC(C)C.Br[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH:38]=2)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)CCS>>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=[C:30]2[CH2:29][NH:15][C:16]1[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCCC(C)C)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: CC(C)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3-methylbutylsulfanylmethyl)-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 28 μL of 3-methyl-1-butanethiol reacted to give 3 mg of the title compound as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[N:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: Nc1cc(O)ccc1F
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1F
Yield: 39.3 %

Procedure:
Using a procedure analogous to Example A3, 3-amino-4-fluorophenol (0.127 g, 1.0 mmol) and 5-bromo-2-nitropyridine (0.203 g, 1.0 mmol) were combined to afford 2-fluoro-5-(6-nitropyridin-3-yloxy)benzenamine (0.098 g, 39% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=2.8 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.8 Hz, 1H), 7.07 (m, 1H), 6.53 (dd, J=7.6, 3.2 Hz, 1H), 6.31 (s, 1H), 5.48 (s, 2H); MS (ESI) m/z: 250.0 (M+H+).