Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:13]=[C:11]([C:10]([OH:15])=[O:14])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 107 °C

Procedure:
Route B: A mixture of 6-chloro-4-iodopyridin-3-ylamine (Preparation 106, 0.33 g, 1.30 mmol), pyruvic acid (0.27 mL, 3.89 mmol), DABCO (0.44 g, 3.89 mmol) and palladium acetate (0.015 g, 0.07 mmol) in dry DMF was stirred vigorously and degassed with argon for 15 min. The reaction mixture was heated to 107° C. for 5 h. The reaction mixture was allowed to cool to rt and stirred for 16 h. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organics were extracted with aqueous NaOH (2M, 3×70 mL). The combined aqueous extracts were acidified to pH 4 by careful addition of glacial acetic acid, then extracted with ethyl acetate (3×60 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a brown solid. RT=2.72 min, m/z (ES+)=197 [M+H]+
Reaction SMILES: Br.[O:2]=[C:3]1[NH:8][CH2:7][C:6]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:5][CH2:4]1.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)#[N:15]>N1C=CC=CC=1>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:11]2[CH2:12][CH2:13][C:6]3([O:5][CH2:4][C:3](=[O:2])[NH:8][CH2:7]3)[CH2:9][CH2:10]2)=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C1COC2(CCNCC2)CN1
Agent: Br
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)CNC(=O)CO3)cc1
Temperature: 25 °C

Procedure:
18.0 g (71.7 mmol) 3-oxo-1-oxa-4,9-diaza-spiro[5.5]undecane hydrobromide (prepared according to J. Med. Chem. 1983, 26, 855) were dissolved in 300 ml dry pyridine, and 11.9 g (71.9 mmol) 4-cyanobenzoyl chloride were added in small portions. The mixture was stirred over night at room temperature and evaporated under reduced pressure. The residue was dissolved in toluene, which was removed in vacuo. This process was repeated two times to remove remaining pyridine. It was treated with water and neutralized by addition of saturated aqueous sodium bicarbonate solution. The precipitate of the title compound was filtered with suction, washed with water, and dried in vacuo.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: OC1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(O)CC5)c34)cc2C)cn1
Yield: 25 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 25% yield; NMR Spectrum: 1.35-1.39 (m, 2H), 1.67-1.69 (m, 2H), 2.15-2.19 (m, 2H), 2.19 (s, 3H), 2.43 (s, 3H), 2.77-2.82 (m, 4H), 3.39-3.42 (m, 1H), 4.42 (t, 2H), 4.53 (br s, 1H), 6.95 (d, 1H), 7.18-7.24 (m, 2H), 7.60-7.63 (m, 2H), 8.17 (s, 1H), 8.30 (s, 1H), 8.33 (s, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.[C:33]1([O:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40](=[O:41])[O:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:7]=3)=[C:10]([F:32])[CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (500 mg, 1.10 mmol) in DCM/pyridine (50 mL/25 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (450 mg, 2.90 mmol) in DCM (5 mL) was added to the mixture slowly over 0.5 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (250 mL). The mixture was washed with water (150 mL×3), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=150/1) to give the title compound as a white solid (352 mg, 46%).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:43][C:44](=[O:54])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:46])[CH3:42].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:43][C:44](=[O:54])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH:46][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[CH3:42]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and L-phenylalanine ethylester hydrochloride (690 mg, 3 m mole) were suspended in DMF (10 ml) and WSC (0.5 ml) were added thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution, ethyl acetate (100 ml) was added, and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-phenylalanine ethylester (1.3 g). The oily material gave a single spot with Rf 0.7 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1O
Yield: 99 %

Procedure:
(E)-Methyl 2-(2'-benzyloxyphenyl)-3-methoxyacrylate (5.44 g) was dissolved in ethyl acetate (50 ml) and 5% palladium on carbon (0.25 g) was added. The stirred mixture was hydrogenated at three atmospheres pressure, with stirring, until no more hydrogen was taken up, then filtered through celite and silica gel (50 g, Merck 60). Concentration of the filtrate under reduced pressure afforded (E)-methyl 2-(2'-hydroxyphenyl)-3-methoxyacrylate as a white crystalline solid (3.76 g; 99% yield), mp. 125°-126° C.; infrared max. (nujol mull): 3400, 1670 cm-1 ; 1H NMR (270 MHz): delta 3.80 (3H, s), 3.90 (3H, s), 6.20 (1H, s), 6.80-7.00 (2H,m), 7.10-7.30 (2H,m), 7.60 (1H, s)ppm.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH:28]=O)[N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)[N:19]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=Cc1cc2c(nn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(NCc2cc3c(nn2)OCCO3)CC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of phenylmethyl 4-amino-1-piperidinecarboxylate (for a synthesis see WO 2004/058144 Example 99(e)) (14.4 g crude, equivalent to 11 g, 47 mmol) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (for a preparation see Example 6(e)) (6.46 g, 39 mmol) in DCM (200 ml) and MeOH (10 ml) was stirred for 4 h at rt, then cooled in ice as sodium triacetoxyborohydride (12.4 g) was added over 15 min. After stirring for another 2 h, the mixture was treated with aqueous sodium bicarbonate to neutralise. The aqueous phase was extracted with DCM and the organic fractions were dried and evaporated. Chromatography on silica (750 g), eluting with 0-10% MeOH/DCM, gave the product (11.1 g, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9]I>CN(C=O)C.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([CH3:9])[CH:4]=1
Reactant: CI
Reactant: Oc1ccc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-5-bromo-pyridine (3.00 g, 17.3 mmol) in anhydrous DMF (25 mL) is added MeI (2.95 g, 20.76 mmol, 1.2 eq.). The mixture is stirred overnight at rt. The solution is diluted with EtOAc (200 mL) and extracted with H2O (4×100 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by silica gel chromatography eluting first with hexane/acetone (4:1) followed by elution with hexane/acetone (1:1) to yield the title compound. MS (+VE) m/z 188.02 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:23][CH2:22][CH2:21][C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(NCCc2ccc(Cl)cc2)n1

Procedure:
A mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylthio] acetic acid ethyl ester, 6.2 g of p-chlorophenethylamine, and 4.24 g of sodium carbonate in 150 ml. of ethanol was heated under reflux for 15 minutes. The reaction mixture was filtered and the filtrate was cooled in ice. The crystalline product which was deposited was collected and recrystallized from ethanol giving 3.6 g of product, mp. 105°-108°C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>C(#N)C>[CH2:28]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[C:6]([F:17])=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 60), 314 (82), 288 (bp), 286 (31), 96 (36).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NC(=O)Cc2ncccc2F)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Temperature: 120 °C
Yield: 65 %

Procedure:
A mixture of 2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (9.01 g, 24.3 mmol) and CDI (15.78 g, 97 mmol) in toluene (97 mL) was heated at 120° C. for 7 h. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 20-100%), to provide 5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid (6.26 g, 65% yield). Mass spectrum m/z 397 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.11 (dd, J=7.6, 0.8 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.8, 1.4 Hz, 1H), 6.85-6.76 (m, 1H), 6.35 (td, J=7.4, 5.0 Hz, 1H), 6.09 (s, 1H), 2.36 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [CH:1]([NH:4]/[C:5](/SC)=[CH:6]/[C:7]#[N:8])([CH3:3])[CH3:2].O.[NH2:12][NH2:13]>CCO>[CH:1]([NH:4][C:5]1[CH:6]=[C:7]([NH2:8])[NH:13][N:12]=1)([CH3:3])[CH3:2]
Reactant: CS/C(=C\C#N)NC(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cc(N)[nH]n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of (Z)-3-(isopropylamino)-3-(methylthio)acrylonitrile (0.413 g, 2.64 mmol) and hydrazine monohydrate (0.38 mL, 7.93 mmol) in EtOH (6 mL) was heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography, eluting with ethyl acetate, DCM/MeOH (9:1) to give N3-isopropyl-1H-pyrazole-3,5-diamine (0.231 g, 62% over 2 steps) as an oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:40][NH2:41].CO>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[N:16]=2)[CH2:11][C:12]([NH:41][OH:40])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1
Reactant: C[Si](C)(C)ON
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2ncc[nH]2)no1)NO
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1H-imidazol-2-ylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 103) (200 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 ml) was treated with 1,1′-carbonyidiimidazole (77 mg, 0.48 mmol) and stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (160 μl, 1.30 mmol) was added and the mixture was stirred for 18 hours. The mixture was then treated with methanol (4 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 90:10:1 (dichloromethane:methanol:ammonia) to afford a colourless oil which began to crystallise once a little methanol and dichloromethane were added. The solid was triturated with dichloromethane and dried under reduced pressure to afford the title compound as a solid (49 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][C@@H:15]([N:26]1[CH:30]=[C:29]([C:31]([NH2:33])=[O:32])[N:28]=[CH:27]1)[C@@H:16]([O:18][Si](C(C)(C)C)(C)C)[CH3:17])[CH:6]=[CH:5]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][C@@H:15]([N:26]1[CH:30]=[C:29]([C:31]([NH2:33])=[O:32])[N:28]=[CH:27]1)[C@@H:16]([OH:18])[CH3:17])[CH:6]=[CH:5]2
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCOc1ccc2cc(Br)ccc2c1)n1cnc(C(N)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](CCOc1ccc2cc(Br)ccc2c1)n1cnc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To an ice cooled solution of 1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide (120 mg, 0.225 mmol) in THF (5 ml) was added dropwise 1.0 M tetra-n-butylammonium fluoride in THF (338 μl). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 2 hours. The reaction was quenched by addition of 25% aqueous AcONH4 (5 ml) and H2O (10 ml) The resulting mixture was stirred for several minutes and then extracted with ethyl acetate (30 ml). The organic layer was washed with brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel (4 g) column chromatography eluting with chloroform/methanol (100:1 to 20:1) to give 1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (16) (58.6 mg, 62.2%) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][C:24]([O:27][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)=[CH:23][C:21]=2[N:22]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2s1
Yield: 69.7 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (355 mg, 1.08 mmol), 2-methyl-1,3-benzothiazole-5-ol (286 mg, 1.73 mmol), potassium carbonate (448 mg, 3.24 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 95, the title compound (275 mg, 70%) was obtained as a pale-yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[C@H:10]([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Li])CCC.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][C:20]([CH3:25])=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[CH:15]=2)[C@H:10]([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(F)cc2ccoc12
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2cc(F)cc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2o1
Reaction time: 0.08 h

Procedure:
A solution of 0.100 gm (0.3 mMol) (−)-cis-1-(tert-butoxycarbonyl)-3-methyl-4-(5-fluorobenzofur-7-yl)piperidine in 2 mL tetrahydrofuran was cooled to −78° C. To this solution were added 0.38 mL (0.6 mMol) n-butyllithium (1.6 M in hexane) dropwise. After stirring for 5 minutes, 0.02 mL (0.33 mMol) iodomethane were added and the reaction mixture was stirred at −78° C. for 3 hours. The solution was treated with an additional 0.06 mL (0.1 mMol) n-butyllithium (1.6 M in hexane) followed by 0.02 mL (0.33 mMol) iodomethane. After stirring for 1 hour at −78° C., an additional 0.06 mL (0.1 mMol) n-butyllithium (1.6 M in hexane) followed by 0.02 mL (0.33 mMol) iodomethane were added to the reaction mixture. The mixture was then stirred at room temperature for 14 hours and was then partitioned between 5 mL deionized water and 40 mL ethyl acetate. The organic phase was washed sequentially with 20 mL portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure to provide (−)-cis-1-(tert-butoxycarbonyl)-3-methyl-4-(2-methyl-5-fluorobenzofur-7-yl)piperidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.O>[CH2:3]([O:10][C:11]([N:13]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1)[CH3:14])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.15 g, 3.8 mmole) was added portionwise, allowing for gas evolution, to a solution of 3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole (0.7 g, 2.5 mmole) in DMF (25 mL) at 0° C. When the NaH addition was complete, benzyl bromide (1.2 mL, 10.0 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (0.9 g, 93%) as an off white solid: MS (ES) m/e 385 (M+H)+.