Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30](O)=[O:31])[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[O:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30](=[O:31])[N:46]3[CH2:45][CH2:44][N:43]([CH:40]4[CH2:41][CH2:42][O:37][CH2:38][CH2:39]4)[CH2:48][CH2:47]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc2nc[nH]c12

Procedure:
Prepared analogously to Example 1h from 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 50 mg (0.29 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])=[O:19]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc(F)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(173 mg, 26%). EI-MS m/z 325 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Product: CN(C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (53%, crystals). HPLC-MS m/z=389.1 (M+1), Rt: 5.1 min.
Reaction SMILES: [OH-].[Li+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([O:15]C)=[O:14]>O.CO>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of lithium hydroxide (20.0 mg, 0.84 mmol) in water (1 mL), methyl quinoline-2-carboxylate (20.0 mg, 0.11 mmol) in methanol (3 mL) was added. The solution was left to stir at room temperature for 2 h. The solution was then concentrated in vacuo. The yellow solid residue was dissolved in water and made acidic with concentrated hydrochloric acid. The organic material was extracted with ethyl acetate. The organic layers were dried with anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield quinoline-2-carboxylic acid as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])=[CH:12][C:11]=1[Cl:17])(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1Cl
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(F)cc2F)cc1Cl

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-chlorophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 26.4, 29.5, 41.2, 62.1, 104.9 (t, J 26.0), 112.3 (dd, J 21.3, 2.9), 122.3 (dd, J 12.7, 3.9), 127.5, 131.3, 131.5, 131.5, 131.7 (d, J 2.0), 136.2, 140.6, 159.9 (dd, J 252.0, 11.7) and 163.3 (dd, J 252.0, 11.7).
Reaction SMILES: [K].O[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7]CC)=O.Cl.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]1[C:5](=[O:7])[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:3][NH:19]1
Reactant: CCOC(=O)C(=CO)c1ccccc1
Reactant: NNc1ccccn1
Agent: Cl
Agent: [K]
Solvent: CCO
Product: O=c1c(-c2ccccc2)c[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
22.7 g (0.1 mol) of the potassium salt of ethyl α-hydroxymethylene-phenylacetate and 18.2 g (0.1 mol) of 2-hydrazino-pyridine dihydrochloride in 200 ml of ethanol are stirred for 30 minutes at room temperature and then boiled under reflux for 5 hours. After the mixture has been cooled to room temperature, 19.1 g (1.7 mol) of potassium tert.-butylate are introduced in portions while nitrogen is simultaneously passed over the mixture. The mixture is stirred for 4 hours at room temperature and left to stand overnight. The precipitate formed is filtered off under suction and suspended in 100 ml of water, and the suspension is slightly acidified with acetic acid. The crystals are filtered off under suction, washed with water and dried in the air. 17.2 g (72.5% of theory) of 1 -pyrid-2-yl-4-phenyl-pyrazoline-5-one of melting point 132° to 133° C. (ethanol) are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][SH:23]>C(#N)C.O.Cl>[Cl:1][C:2]1[C:7]2[C:8]([OH:10])=[C:22]([C:21]([O:25][CH2:26][CH3:27])=[O:24])[S:23][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Reactant: CCOC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1sc2cc(C)nc(Cl)c2c1O
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a suspension of ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (10.0 g, 42.7 mmol) in acetonitrile (45 mL) were added potassium carbonate (8.85 g, 64.1 mmol) and ethyl thioglycolate (4.68 mL, 42.7 mmol), and the mixture was stirred for 15 hr under refluxing conditions. The reaction mixture was diluted with water (150 mL), 6N hydrochloric acid (15 mL) was added and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water and ethanol-diisopropyl ether (1/1), and dried under reduced pressure to give the title compound (10.9 g, 94%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])=[C:7]([F:16])[C:8]2[N:9]([C:11]([C:14]#[CH:15])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]>[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])=[C:7]([F:16])[C:8]2[N:9]([C:11]([CH2:14][CH3:15])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: C#Cc1cnc2c(F)c(Nc3ccc(C)cc3F)c(C(=O)OC)cn12
Agent: [Pd]
Product: CCc1cnc2c(F)c(Nc3ccc(C)cc3F)c(C(=O)OC)cn12
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A mixture of 3-ethynyl-8-fluoro-7-(2-fluoro-4-methylphenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (16 mg, 0.047 mmol) and 10% Pd/C (5 mg) under an atmosphere of hydrogen (balloon) was stirred vigorously for one hour. The mixture was filtered through a plug of rinsing with dichloromethane and concentrated to provide the desired product (14 mg, 86%) as a yellow foam. MS APCI (+) m/z 346 (M+1) detected. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.31 (s, 1H), 7.38 (s, 1H), 6.91 (d, 1H), 6.84 (s, 2H), 3.97 (s, 3H), 2.86 (q, 2H), 2.30 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:16]=[C:15]([F:17])[CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[CH2:23].CCN(C(C)C)C(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([N:6]1[C:5]2[N:20]=[CH:21][C:2]([CH2:23][CH2:22][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][C:15]([F:17])=[N:16][C:7]1=2)[CH3:19]
Reactant: C=Cc1ccc2ccccc2c1
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1c2ncc(CCc3ccc4ccccc4c3)cc2C(=O)N(C)c2ccc(F)nc21

Procedure:
8-Bromo-2-fluoro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (35 mg, 0.10 mmol) was coupled with 2-vinylnaphthalene in the presence of bis(triphenylphosphine)palladium(II) chloride and (i-Pr)2NEt as described in example 1h. The product was hydrogenated as described in example 3b. Purification by flash chromatography (elution with ethyl acetate-hexanes) and recrystallization (diethyl ether-hexanes) afforded 20 mg of the title compound as white crystals, m.p. 112°-114° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C)C=O>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:18]2[CH2:17][CH2:16][N:15]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:20][CH2:19]2)=[CH:26][CH:25]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C(C1CCN(c2ccncc2)CC1)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(1-(4-Pyridyl)piperidin-4ylcarbonyl)piperazine (0.722 g) was dissolved in dry dimethylformamide (22 mL) and treated with sodium hydride (0.19 g, 45-55% dispersion, 4 mmol) under argon atmosphere. The resultant mixture was then allowed to stir for 30 minutes before the addition of 4-bromobenzyl bromide (0.66 g). The reaction was then stirred at room temperature for 2 hours and then quenched by pouring into water, basifying with saturated aq.NaHCO3 and then extracting with diethyl ether. The combined organic extracts were then washed with water, brine, dried (MgSO4) and then evaporated to afford a crude, cream solid which was then recrystallised twice from ethyl acetate/isohexane to give 4-(4-bromophenylmethyl)-1-(1-(4-pyridyl)piperidin-4-ylcarbonyl)piperazine as a white solid; m.p. 148-149° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:16][CH:17](C)[C:18]([C:20]1C=CC(Br)=CC=1C)=O.C([Mg]Br)C>>[Br:16][CH:17]([CH2:18][CH3:20])[C:4]([C:3]1[CH:7]=[CH:8][C:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: Cc1cc(Br)ccc1C(=O)C(C)Br
Reactant: O=C(O)c1ccc(-n2cncn2)cc1Cl
Agent: CC[Mg]Br
Product: CCC(Br)C(=O)c1ccc(-n2cncn2)cc1Cl

Procedure:
This compound is prepared from 2-chloro-4-[1,2,4]triazol-1-yl-benzoic acid analgously to 2-bromo-1-(4-bromo-2-methyl-phenyl)-propan-1-one (Intermediate MA) by replacing ethylmagnesium bromide with the appropriate alkyl magnesium bromide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=O.CC1C(C)=CC=CC=1NO.[CH3:22][N:23]([NH2:25])[CH3:24]>>[CH3:22][N:23]([CH3:24])[N:25]=[N+:9]([O-:11])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: CN(C)N
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: Cc1cccc(NO)c1C
Product: Cc1cccc([N+]([O-])=NN(C)C)c1C

Procedure:
Similarly 12.1 g. of 2,3-dimethylnitrobenzene was hydrogenated to 2,3-dimethylphenylhydroxylamine, which was oxidized with ferric chloride to the nitroso compound. This compound was treated with unsymmetrical dimethylhydrazine to yield 3,3-dimethyl-1-(2,3-dimethylphenyl)triazene-1-oxide.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.[C:20](N1C=CN=C1)([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[S:21].Cl>C1COCC1>[N:22]1([C:20]([N:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:3]([O:2][CH3:1])[CH2:4]2)=[S:21])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=S)n2ccnc2)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
Benzyl cis(±)-4-(3-methoxypiperidin-4-yl)-carbamate obtained by the method described in Example (40b) (735 mg, 1.37 mmol) was dissolved in THF (8 mL). 1,1′-Thiocarbonyldiimidazole (270 mg, 1.36 mmol) was added, and the mixture was stirred for 1.5 hours. 0.5 M hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([O:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1>O1CCOCC1>[F:28][C:3]([F:2])([F:27])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCCC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)CCOc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4M HCl in dioxane (10 mL) was added to tert-butyl 4-[4-(3,3,3-trifluoropropoxy)phenoxy]piperidine-1-carboxylate (550 mg). The mixture was stirred at ambient temperature for 10 minutes. The mixture was then concentrated at reduced pressure and triturated with diethyl ether and stirred for 10 minutes. The resulting precipitate was filtered and dried under vacuum to give 4-[4-(3,3,3-trifluoropropoxy)phenoxy]piperidine as the hydrochloride salt (286 mg); NMR Spectrum: (DMSOd6) 1.76-1.88 (m, 2H), 2.01-2.12 (m, 2H), 2.66-2.82 (m, 2H), 2.97-3.10 (m, 2H), 3.14-3.27 (m, 2H), 4.15 (t, 2H), 4.46-4.56 (m, 1H), 6.87-6.98 (m, 4H), 9.03 (bs, 2H); Mass Spectrum: M+H+ 290.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH3:32])[C:23]=1[CH2:33][CH2:34][CH3:35]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH3:32])[C:23]=2[CH2:33][CH2:34][CH3:35])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.471 g) in dimethylformamide (10 mL) was treated with 55% sodium hydride (0.117 g), stirred for 15 minutes and then a solution of with 1-[4-(3-bromopropoxy)-2-methoxy-3propylphenyl]ethanone (0.8 g) in dimethylformamide (5 mL) was added. The mixture was heated at 50° C. for 17 hours and worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-hexane; 1:4), followed by flash chromatography over silica gel (ethyl acetate-toluene; 1:19) to yield 0.4 g of 4-[3-[4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10]>C(Cl)Cl>[O:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccccn1)C(F)(F)F
Yield: 28 %

Procedure:
In analogy to GP 2, reaction of 4.5 g Intermediate 3 (17.6 mmol, 1 eq.), 2.13 mL dry pyridine (26.4 mmol, 1.5 eq.), 4.45 ml trifluoromethanesulfonic acid anhydride (26.4 mmol, 1.5 eq.) in 140 mL DCM yielded 2.9 g 2-pyridyl triflate (7.4 mmol, 42% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].[CH2:11](Br)[CH:12]=[CH2:13].Cl>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH2:13][CH:12]=[CH2:11])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: C=CCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
The corresponding arylmagnesium bromide was prepared from 406 g (1.94 mol) of 4-bromo-2-chlorofluorobenzene and 48.6 g (2.00 mol) of magnesium turnings in 1,300 ml of anhydrous tetrahydrofuran by the customary process. The solution thus obtained was added dropwise to a solution of 278.3 g (2.3 mol) of allyl bromide in 200 ml of anhydrous tetrahydrofuran at 30°-45° C. The mixture was then heated under reflux for 0.5 h, allowed to stand at room temperature for 16 h and poured onto 1.5 liters of ice-water. After acidification using a little 2N hydrochloric acid, the mixture was extracted twice using 1 liter of hexane each time. The extracts were washed three times with water, dried over Na2SO4 and evaporated. The residue yielded 235 g (71%) of 3-(3-chloro-4-fluorophenyl)propene of b.p.10 =72° C. with a purity of 98.7% (determined by gas chromatography) on subsequent distillation.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][S:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:22]4[CH2:28][C@H:25]3[CH2:24][S:23]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1S[C@@H]2CN[C@H]1C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2C[C@H]1CS2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane hydrochloride (125136-43-8) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.5 [MH+].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][C:23](C)(C)C)=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a cooled (0° C.) solution of (rac)-tert-butyl 2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetate (example 97) (102 mg, 0.26 mmol) in MeOH (4 mL) was added 4M HCl in dioxane (0.26 mL, 1.04 mmol) and the reaction mixture was stirred at room temperature for 16 h. The solution was cooled (0° C.) again and treated with 4M HCl in dioxane (0.39 mL, 1.56 mmol). After 1 h at room temperature, the solution was evaporated to dryness. The residue was suspended in EtOAc, filtered and dried to give the title compound (46 mg, 51%, 80% purity with 20% of corresponding acid) as a grey solid. MS: 352.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[N+:28]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)([O-:30])=[O:29]>CN(C=O)C>[CH:18]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[N+:28]([O-:30])=[O:29])[CH:12]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4[N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (2.00 g, 7.13 mmol) in DMF (36.7 mL) was charged with Cs2CO3 (3.48 g, 10.7 mmol) and stirred at rt for 30 min. A DMF solution of 2-nitrobenzyl bromide (1.54 g, 7.13 mmol), was then added to the reaction mixture. The reaction was allowed to progress at rt under nitrogen for 3.5 h. TLC analysis showed that the reaction was complete. The product was purified using silica gel column chromatography (1-3% NH3 in MeOH:CH2Cl2). The final product was concentrated to a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.08 (m, 1H), 2.11-2.23 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.86 (m, 1H), 5.57 (s, 2H), 7.01-7.05 (m, 2H), 7.11 (d, J=5.6 HZ, 1H), 7.27-7.30 (m, 1H), 7.32-7.33 (m, 1H), 7.42 (t, J=16.4 Hz, 1H), 7.48-7.52 (m, 1H), 7.67-7.71 (m, 1H), 7.92 (dd, J=8.0 Hz, 1H), 8.17 (d, J=9.5 Hz, 1H); MS (ES+): m/z 416.01 (100) [MH+].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([CH2:31][CH2:32][CH2:33][CH3:34])[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[CH:5]1[C:35]([O:37]C)=[O:36])(=[O:3])[CH3:2].[OH-].[Na+:40]>CO>[Na+:40].[Na+:40].[CH2:31]([C:11]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]2[CH:5]([C:35]([O-:37])=[O:36])[N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][C:7]=2[N:10]=1)[CH2:32][CH2:33][CH3:34].[CH2:31]([C:11]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]2[CH:5]([C:35]([O-:37])=[O:36])[N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][C:7]=2[N:10]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(C)=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)[O-])N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in Example 4 (142 mg), 1N aqueous sodium hydroxide solution (0.60 ml) and methanol (5 ml) is stirred at room temperature overnight, and evaporated under reduced pressure to remove the solvent. The resulting residue is purified by column chromatography of nonionic adsorbing resin (tradename; HP-20, manufactured by Mitsubishi Kasei Corporation, Japan), and lyophilized to give 2-n-butyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylic acid disodium salt (100 mg).