Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:21]([NH:23][CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([O:32][CH3:33])([CH3:31])[CH3:30])[CH3:22]>C(OCC)C.CN(C)C=O>[CH2:21]([N:23]([CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([O:32][CH3:33])([CH3:30])[CH3:31])[CH3:22]
Reactant: CCNC/C=C/C#CC(C)(C)OC
Reactant: O=Cc1ccc(CO)o1
Agent: BrP(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
0.36 g of 5-hydroxymethyl-2-furaldehyde was dissolved in 10 ml of ethyl ether, and under a nitrogen atmosphere, a ethyl ether solution (2 ml) of 0.25 g of phosphorus tribromide was added dropwise at 0° C. After the mixture was stirred at room temperature for 30 minutes, 0.70 g of potassium carbonate and a dimethylformamide solution (15 ml) of 0.62 g of (E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine hydrochloride were added. The mixture was stirred overnight at room temperature, and then worked up in a customary manner. The product was purified by silica gel column chromatography [hexane/ethyl acetate=2/1] to give 0.62 g of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-5-formyl-2-furylmethylamine as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.CO>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCCCC4)cc3)nc2CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(1-piperidinyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 33) (70 mg, 0.18 mmol) in dioxan (1 ml) was added 4M hydrochloric acid in dioxan (2 ml). The resulting mixture was stirred at room temperature, under argon, overnight. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D43). MS (ES+) m/e 297 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[Br:35][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccc3ncc(C(C)c4ccc5nccn5c4)n3n2)c1
Solvent: ClCCl
Product: Cc1cccc(-c2ccc3ncc(C(C)c4ccc5ncc(Br)n5c4)n3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-m-tolyl-imidazo[1,2-b]pyridazine (Example 308, 100 mg, 0.283 mmol) was dissolved in DCM (2.8 mL) and NBS (50.4 mg, 0.283 mmol) was added. It was stirred at rt for 1 h then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated. The residue was repurified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford the title compound after evaporation of the solvent as a white solid. (tR 1.0 min (conditions 2), MH+=432).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[O:14]CC.C(Cl)(=O)C>CCCCCC>[CH2:11]([C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1)[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: CCc1ccc(N)c(C(=O)O)c1
Solvent: CCCCCC
Solvent: CC(=O)Cl
Product: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 83.3 %

Procedure:
A mixture of 2-amino-5-ethylbenzoic acid (20.28 g) and ethyl chlorocarbonate (53.5 g) was stirred for 50 minutes at 100° C. and then cooled to 90° C. To the mixture was added dropwise acetyl chloride (13.81 g) in the course of 15 minutes and the reaction mixture was stirred for 2 hours at 100° C. After the resultant mixture was cooled to ambient temperature, to the mixture was added hexane and allowed to stand at ambient temperature to give crystals, which were separated by filtration, washed with hexane and dried under reduced pressure to give crystalline 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15].[OH-].[K+]>O>[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12)[NH2:15]
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C

Procedure:
543 mg (3.56 mmol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine (from example XVIII, 905 mg (7.12 mmol) of 3-fluoro-4-hydroxyaniline and 399 mg (7.12 mmol) of powdered potassium hydroxide are heated at 260° C. for 8 hours. Another 905 mg (7.12 mmol) of 3-fluoro-4-hydroxyaniline and 200 mg (3.56 mmol) of powdered potassium hydroxide are added, and the mixture is reacted at 260° C. for another 8 h. For work-up, the mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC. The fractions which, according to LC-MS, contain 39% of product are used without further purification for the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([C@H:29]([CH2:31][CH3:32])[CH3:30])[NH2:28].C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>ClCCl>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([C@H:29]([CH2:31][CH3:32])[CH3:30])[NH:28][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC
Yield: 81 %

Procedure:
N-Benzyloxycarbonyl-L-phenylalanine (3.0 g) and L-isoleucine methyl ester hydrochloride (1.82 g) are dissolved in anhydrous dichloromethane (30 ml), and thereto are added triethylamine (2.80 ml) and further 1-methanesulfonyloxy-1,2,3-benzotriazole (2.15 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 40 hours. After reaction, the solvent is distilled off and the resulting residue is extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium hydrogen carbonate (5 times), water, 2 N hydrochloric acid and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give crystalline powder of N-(N-benzyloxycarbonyl-L-phenylalanyl)-L-isoleucine methyl ester (3.46 g), melting point: 94.5°-95.5° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:31])=[C:5]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].Cl>>[Cl:1][C:2]1[S:3][C:4]([Cl:31])=[C:5]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(=O)c2cccc(Cl)c2)cc1
Agent: Cl
Product: C[C@H](NC(=O)c1c(Cl)sc(Cl)c1C(=O)c1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-[(1S)-1-({[2,5-dichloro-4-(3-chlorobenzoyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 10, Step 1 (73.0 mg, 0.147 mmol) was reacted under conditions similar to Example 1, Step 11. The reaction mixture was neutralized with 25% aq. NH4OAc (instead of an acidification with 1N HCl). The crude was purified by chromatography on silica gel (35:65 EtOAc/hexane containing 0.25% AcOH) to afford the desired product as an off-white solid. MS (−APCI): m/z 480 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH:15]1[CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[CH:14]3[CH2:16][CH:15]3[CH3:17])=[CH:3][C:2]=2[F:1])[CH2:27]1)[CH3:23]
Reactant: CCNCC1CCNC1
Reactant: CC1CC1n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4C)c3c2F)C1
Yield: 80.6 %

Procedure:
To 0.75 g (2.57 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(2-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.38 g (2.57 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.32 g (2.57 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for two hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-(2-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid, mp 225°-228° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.63 g, 2.3 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.4 g, 2.53 mmol) according to the general procedure IIb. Obtained as a light yellow solid (0.53 g, 65%). MS (ISP) 351.1 [(M+H)+]; mp 183.5° C.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[NH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+].Cl>C(O)CO.CC(C)=O>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[O:9]
Reactant: Cc1cc(N)cc(C)c1O
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CC(C)=O
Solvent: OCCO
Product: Cc1cc(NC(=O)c2ccccc2O)cc(C)c1O
Temperature: 0 °C

Procedure:
Acetylsalicylic acid (50 mg.) and 4-amino-2,6-dimethylphenol (38 mg.) were dissolved in ethylene glycol (5 ml.) to which under cooling at 0° C. was added dicyclohexyl carbodiimide (65 mg.). After reaction for several hours the formed dicyclohexylurea was filtered off and the filtrate evaporated to dryness to give a powder which was dissolved in acetone (2 ml.); after adding 2 N sodium hydroxide (4 ml.), the solution was allowed to stand for several hours at room temperature. The addition of 2 N hydrochloric acid (20 ml.) gave a precipitate which was collected by filtration, washed with water and dried at 50° C. under reduced pressure to give solid 2,4'-dihydroxy-3',5'-dimethylbenzanilide as a powder which was then purified by column chromatography using Sephadex LH-20 resin and elution with methanol. The eluate was evaporated to dryness to give a solid which was recrystallized from aqueous acetone to give white crystals (57.8 mg.) of 2,4'-dihydroxy-3',5'-dimethylbenzanilide. Yield: 80.9%. Melting point: 142°-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCCC3)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC=C3)cc1

Procedure:
A solution of N-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)-2,2,2-trifluoro acetamide (10.7 g, 31.1 mmol), N-bromosuccinimide (6.6 g, 37 mmol), and AIBN (200 mg, 1.2 mmol) in CCl4 (300 ml) was stirred at reflux under nitrogen for 1 hour. After coupling the solution was filtered, concentrated in vacuo to a volume of 25 ml, and applied to a column of silica gel. Elution with ethyl acetate:hexane (1:10) gave a mixture of benzylic bromides (10.7 g). A solution of the bromides and Li2CO3 (5.0 g, 68 mmol) in DMF (50 ml) was stirred at 110-120° C. under nitrogen for 3 hours and then overnight at room temperature. The solution was concentrated in vacuo and the residue taken up in methylene chloride (150 ml) and washed with water (50 ml). The aqueous phase was separated, extracted with more methylene chloride (100 ml), and the combined organic solutions were then washed with a small volume of water, dried (K2CO3) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:13) to give N-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoroacetamide and the corresponding 5,6-dihydro isomer in a 3:1 ratio as determined by NMR (4.3 g). 1H NMR (DMSO-d6, 200 MHz) δ: 2.10-2.46 (m, 3H, CH2), 2.63-2.89 (m, 1H, CH2), 6.03-6.22 (m, 1H, CH), 6.41 (dt, J=10,2 Hz, 0.25H, CH), 6.48 (dt, J=10,2 Hz, 0.75H, CH), 7.08-7.33 (m, 3H, Ar), 7.41 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O: C, 66.67; H, 3.83; N, 8.18. Found: C, 66.55; H, 3.86; N, 8.10.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])C)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>ClCCl>[Br:17][C:8]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][NH:9]1
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CC1=CNC(Br)(Oc2ccccc2)N=C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B, 400 mg, 1.87 mmol) in dichloromethane (14 mL) was added tetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. overnight and allowed to cool to room temperature. Hexane (4 mL) was subsequently added. After three hours and little precipitation, additional (150 mg) tetrabutylammonium tribromide was added and the reaction mixture was stirred overnight at room temperature. The pale yellow precipitate that formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (375 mg, 68%); Rf 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 295, 293 (M+1, Br isotopes).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C)C=O>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 13 h
Yield: 65.5 %

Procedure:
In an argon atmosphere, 5-nitrosalicylaldehyde (334 mg, 2.00 mmol) was dissolved in dimethyformamide (5 mL), and the solution was mixed with benzyl bromide (0.238 mL, 2.00 mmol) and sodium hydride (88 mg, 2.4 mmol), followed by stirring at 70° C. for 13 hours. The reaction solution was cooled with ice, and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to obtain 2-benzyloxy-5-nitrobenzaldehyde (337 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Br:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(Br)cc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 52.1 %

Procedure:
197 mg (0.70 mmol) of 3,5-dibromobenzoic acid (prepared according to J. Organometallic Chem. 215, 281 (1981)) are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) of triethylamine to give the title compound (168 mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.60, FD-MS: M+ =687, 689, 691.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:22][S:23]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:25])=[O:24].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:33][CH2:32]1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
1-Ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (1.0 g, 5.0 mmol) was dissolved in DMSO (8 mL). Potassium carbonate (2.1 g, 15 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (1.1 g, 5.0 mmol) were added and the reaction mixture was heated to 65° C. and allowed to stir over the weekend. The mixture was then poured into water and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo to give the title compound without further purification (1.7 g, 4.7 mmol, 93%). MS (M+H, ES+) 372.
Reaction SMILES: [Br-].[Li+].C(N(CC)CC)C.[F:10][C:11]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:12]=1[CH2:13][CH:14]1[CH2:19][CH:18]([C:20]([O:22]C)=[O:21])[CH2:17][CH2:16][N:15]1[C:24]([O:26][CH3:27])=[O:25].CC(OC)(C)C>C(#N)C.O>[F:10][C:11]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:12]=1[CH2:13][CH:14]1[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17][CH2:16][N:15]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(F)cc1F
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a suspension of lithium bromide (18.06 g, 207.99 mmol) in acetonitrile (80 mL) and water (1.6 mL) was added triethylamine (14.42 mL, 104.00 mmol) followed by dimethyl 2-(2,4-difluorobenzyl)piperidine-1,4-dicarboxylate (8.51 g, 26.00 mmol) in acetonitrile (40 mL). The resulting mixture was heated under reflux for 2 h 30 min, then cooled to room temperature and water and MTBE were added. The organic phase was extracted with water twice. The pooled aqueous layers were adjusted to pH 1 with 3.8 M HCl and then extracted with DCM (3×). The combined organic layers were dried over MgSO4 and evaporated to yield 2-(2,4-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.48 g, 92%) as an orange solid. MS m/z 314 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-])=[C:5]([CH3:12])[CH:4]=1.C(OC(=O)C)(=[O:15])C>>[OH:15][CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)[n+]([O-])cc1OC
Product: COc1cnc(CO)cc1OC
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
19 g of 4,5-dimethoxy-2-methylpyridine 1-oxide are metered into 60 ml of acetic anhydride, warmed to 80° C., in the course of 30 minutes in a manner such that the temperature does not rise above 100° C. After a further 45 minutes at 85° C., excess acetic anhydride is distilled off in vacuo and the oily dark residue, which essentially consists of the intermediate 2-acetoxymethyl-4,5-dimethoxypyridine is stirred with 80 ml of 2N sodium hydroxide solution at 80° C. for 1 hour. After dilution with 80 ml of water and cooling, the mixture is extracted eight times with 100 ml of methylene chloride each time, the combined organic phases are washed twice with 1N sodium hydroxide solution, dried and concentrated and the crystalline, brownish residue is recrystallized from toluene. 14 g (74% of theory) of 2-hydroxymethyl-4,5-dimethoxy-pyridine of m.p. 122°-24° C. are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:14])[CH2:12]Cl)=[C:8]([CH3:15])[S:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:12][C:11]([NH:10][C:9]3[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][C:8]=3[CH3:15])=[O:14])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1csc(C)c1NC(=O)CCl
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: Cc1scc(C(=O)O)c1NC(=O)COc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In analogy to Example 2, the title compound was prepared using 4-(2-chloro-acetylamino)-5-methyl-thiophene-3-carboxylic acid methyl ester [23964-99-0] and 4′-fluoro-biphenyl-4-ol. MS (m/e): 384.0 (M−H).