Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:6]=[C:7]2[N:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=13)[S:10][CH:9]([C:17]([OH:19])=O)[CH2:8]2>>[ClH:3].[N:5]1[CH:6]=[C:7]2[N:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=13)[S:10][CH:9]([C:17]([Cl:3])=[O:19])[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1Cc2cnc3cccc(n23)S1
Product: Cl
Product: O=C(Cl)C1Cc2cnc3cccc(n23)S1
Temperature: 60 °C

Procedure:
To a solution of 5.13 g (20.7 mM) of ethyl 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylate in ethanol (20 ml) was added 12 ml (24 mM) of 2N-aqueous solution of sodium hydroxide at room temperature and the mixture was stirred for 1 hour. To this reaction mixture was added 4 ml (24 mM) of 6N-hydrochloric acid and the resulting crystals were collected by filtration. This crystal crop was rinsed with ethanol and diethyl ether to provide 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid as light-brown crystals. This carboxylic acid was not purified but used as it was in the next reaction. To 2.2 ml (30.0 mM) of thionyl chloride was added 661 mg (3.0 mM) of the above 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and the mixture was heated at 60° C. for 1 hour. Then, the excess thionyl chloride was distilled off under reduced pressure and 10 ml of toluene was added to the residue. After thorough mixing, the solvent was distilled off under reduced pressure to provide 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid chloride hydrochloride. To a solution of this acid chloride in 30 ml of THF was added 2.5 ml (40.0 mM) of triethylamine as well as 1286 mg (6.0 mM) of 1-(tert-butoxycarbonyl)-4-aminomethylpiperidine at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured in 50 ml of iced water and extracted with 100 ml of ethyl acetate. The organic layer was washed with 100 ml of saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/ethanol=10/1) to provide 801 mg (yield 64.1%) of the title compound as brown amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:41])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(C)noc4C)cc3)oc2C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl-propionic acid ethyl ester (907 mmol) (see Ex. 2, part B) and 3,5-dimethylisoxazole-4-boronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3 (aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes) to yield the product in 92% yield as an oil; Rf=0.16 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.99 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H), 7.06-7.01 (m, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.4 Hz, 2H), 2.92 (t, J=6.4 Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 1.48 (s, 6H), 1.23 (t, J=7.2 Hz, 3H); MS (EI) 528.2 (M+Na)+, 505.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][Br:12])[CH3:8]>CC(C)=O>[BrH:12].[CH2:7]([O:9][C:10](=[O:13])[CH2:11][N:6]1[CH:5]=[CH:4][S:3][C:2]1=[NH:1])[CH3:8]
Reactant: Nc1nccs1
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Product: Br
Product: CCOC(=O)Cn1ccsc1=N
Yield: 80.4 %

Procedure:
A solution of 2-aminothiazole (27 g, 0.27 mol) and bromo-acetic acid ethyl ester (36 mL, 0.32 mol) in 540 mL of acetone was heated at 50° C. for 6 hours. The mixture was concentrated under reduced pressure and the residue was triturated with ethanol. The solid was collected by filtration to provide 58 g (80%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.25 (t, J=7.1 Hz, 3H), 4.20 (q, J=7.1 Hz, 2H), 5.00 (s, 2H), 7.04 (d, J=4.7 Hz, 1H), 7.38 (d, J=4.7 Hz, 1H), 9.62 (s, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:37][CH2:38][CH2:39]Br)=[C:28]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:37][CH2:38][CH2:39][N:51]4[CH2:50][CH2:49][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:53][CH2:52]4)=[C:28]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Fc1ccc(Nc2ncnc3cc(OCCBr)c(OC4CCCC4)cc23)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OC2CCCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
340 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene are added at ambient temperature to 940 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-bromoethoxy)-quinazoline and 1.00 g of N-(tert.butyloxycarbonyl)-piperazine in 30 ml of acetonitrile. The reaction mixture is heated to 60° C. for five hours. Then a further 0.2 g of N-(tert.butyloxycarbonyl)-piperazine and some 1,8-diazabicyclo[5.4.0]undec-7-ene are added. The yellow reaction solution is stirred for two hours at 60° C. and then overnight at ambient temperature, during which time a white precipitate is formed. This is suction filtered, washed with a little acetonitrile and dried. 453 mg of the desired product are obtained as a white solid. The mother liquor is concentrated by evaporation and the flask residue is chromatographed over a silica gel column with methylene chloride/methanol (95:5). Another 300 mg of the desired product are obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7]CC2O.[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.C(O[C:30](=[O:39])[C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32])(=O)C>>[OH:32][C@@H:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:30]([N:23]([C:3]1[CH:2]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:4]=1)[CH2:22][CH2:21][C:18]1[CH:19]=[N:20][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:16][CH:17]=1)=[O:39]
Reactant: Nc1ccc2c(c1)C(O)CCO2
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: COc1cccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)c1

Procedure:
In analogy to example 55, 6-Amino-chroman-4-ol (as described in WO 2005037830), (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give the target compound. MS(m/e): 473.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](F)[CH:22]=[C:21]3[C:16]=2[C:17](=[O:26])[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][OH:28]>>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:28][CH3:27])[CH:22]=[C:21]3[C:16]=2[C:17](=[O:26])[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCCN1CCC(Oc2cc(F)cc3nc[nH]c(=O)c23)CC1
Reactant: CO
Product: COc1cc(OC2CCN(CCOC(C)(C)C)CC2)c2c(=O)[nH]cnc2c1
Yield: 63.1 %

Procedure:
An analogous reaction to that described in example 137b, but starting with 5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-fluoroquinazolin-4(3H)-one (363 mg, 1 mmol) and methanol (162 μl, 4 mmol) at 110° C. for 2 hours yielded 5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4(3H)-one (237 mg, 63% yield):
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[S:12])#[N:2].[OH-].[Na+].[CH3:24]I>C(O)C>[CH3:8][C:7]1[C:3]2[C:1]([NH2:2])=[N:13][C:11]([S:12][CH3:24])=[N:10][C:4]=2[S:5][C:6]=1[CH3:9]
Reactant: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(N)c2c(C)c(C)sc2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)-benzamide (Example 1a) (1.33 g, 4.22 mmol) in ethanol (25 mL) was added NaOH (2.0 N, 5.8 mL) at room temperature under nitrogen. After stirring at 100° C. under nitrogen for 0.5 h, the reaction mixture was cooled in an ice bath and MeI (0.8 mL) was added dropwise. After stirring for another 0.5 h, the resulting precipitate was collected by filtration, rinsed with water, 20% EtOH/H2O, and dried under vacuum to give the title compound (840 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 2.34 (s, 3H), 2.42 (s, 3H), 6.93 (bs, 2H). MS 226 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]CC)=O)=[CH:11][N:10]=1.[CH:22](OC)=O.[NH2:26][C:27]([NH2:29])=[S:28]>C1COCC1.CCOCC.CC(O)C>[CH3:7][O:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:19])[NH:26][C:27](=[S:28])[NH:29][CH:22]=2)=[CH:13][N:14]=1
Reactant: COC=O
Reactant: NC(N)=S
Reactant: CCOC(=O)CCc1cnc(OC)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice cooled solution of potassium t-butoxide (7.83 g, 0.07 mol) in anhydrous THF (60 ml) was added dropwise with stirring under argon over 1 hour to a solution of ethyl 3-(2-methoxypyrimidin-5-yl)propionate (5.87 g, 0.028 mol) and methyl formate (3.6 ml, 0.059 mol) in anhydrous ether (70 ml). After stirring for 16 h, the solvents were evaporated, thiourea (4.25 g, 0.056 mol) and propan-2-ol (80 ml) added and the mixture refluxed for 5 h. The solvent was evaporated and the residue dissolved in water, extracted twice with ether and acidified to pH 4.5 with acetic acid. The solid which precipitated was filtered, washed well with water and dried, yield 5.57 g (80%). 1H-NMR (d6-DMSO) δ3.47 (2H, s), 3.85 (3H, s), 7.43 (1H, s), 8.48 (2H, s), 12.25 (1H, br s), 12.46 (1H, br s); MS (APCI+) found (M+H)=251; C10H10N4O2S requires 250.
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:22][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:8]1
Reactant: C[C@H]1CCC[C@H](CCc2ccccc2)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CCC[C@H](CCc2ccccc2)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(2-phenylethyl)piperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 65 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(2-phenylethyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 148.3-151.0; 1H NMR (300 MHz) δ 9.3, (s, 2H), 7.28-7.11 (m, 5H), 3.43 (s, 1H), 3.19 (s, 1H), 2.67-1.27 (m, 13H); 13C NMR (75 MHz) 140.0 (s), 128.3 (s), 126.1 (s), 50.9 (s), 47.9 (s), 32.1 (s), 31.5 (s), 28.5 (s), 26.4 (s), 17.2 (s), 16.5 (s). FT-IR (neat): 3410, 3075, 2944, 1590, 1494, 1454, 1435, 1336, 1122, 1029, 751, 701. Elemental Analysis for C14H22NCl: C, 70.11%; H, 9.27%; N, 5.84%. Found: C, 69.95%; H, 9.19%; N, 5.79%.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH2:30]([CH2:32][NH2:33])[OH:31].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([NH:33][CH2:32][CH2:30][OH:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: NCCO
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 721.1 %

Procedure:
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4 above) (1.9 g, 4.10 mmol) was dissolved in 20 ml of CH2Cl2. Ethanolamine (297 μl, 4.92 mmol) was added, followed, in order, by EDCI (0.764 g, 4.92 mmol), 1-hydroxybenzotriazole (0.6659, 4.92 mmol) and triethylamine (1.14 ml, 8.20 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH4Cl and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHCO3 (aq.) and extracted 3 times with ethyl acetate. The organic layers were combined and washed with H2O and extracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2SO4 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (15 g, 72%). 1H NMR (300 MHz, CDCl3) δ 7.93 (dd, J=7.85, 1.61 Hz, 1H), 7.65 (d, J=1.61 Hz, 1H), 7.62 (app q, J=8.26 Hz, 1H), 7.40 (d, J=8.06 Hz, 1H), 7.39-7.30 (m, 1H), 7.03-6.97 (m, 1H), 6.88-6.81 (m, 1H), 6.25 (s, 1H), 5.20 (s, 2H), 3.70-3.52 (m, 1H), 3.16-3.12 (m, 2H), 2.10 (s, 3H), 1.98 (s, 3H); ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0719 (M+H calcd for C23H22BrF2N2O4 requires 507.0726).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]\[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](\[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCCC/C(=C/C=C/C(=O)O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
As in Example 115, (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid (3.3 g) and 4-nitrophenol (2.1 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.67 g) and the mixture was stirred at room temperature for 3 days. After the usual work up. crystallization of the crude material from hexane gave 3.1 g of (2E,4Z)-5-(3-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 50°-51° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([CH2:26][C:27](OC)=[O:28])[CH2:20][CH2:19]2)(=[O:14])[CH3:13]>C(OCC)(=O)C>[OH:28][CH2:27][CH2:26][C:21]1[CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[CH:25]=[CH:24][C:23]=2[CH:22]=1
Reactant: COC(=O)CC1=Cc2ccc(NC(C)=O)cc2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
Lithium aluminum hydride (242 mg, 6.38 mmol) was added to a tetrahydrofuran solution (16 ml) of methyl [6-(acetylamino)-3,4-dihydro-2-naphthalenyl]acetate (827 mg, 3.19 mmol) obtained in Reference Example 101 under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The residue was powdered with isopropyl ether, to give the titled compound (364 mg).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][O:16]2)([C:12]#[N:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N.O>CO.[Ni]>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:12][NH2:13])([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][O:16]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C#N)(CC2CCCO2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)N1CCC(CN)(CC2CCCO2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a heavy wall flask was placed 1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidine-4-carbonitrile (15, 2 g, 6.98 mmol) and 2N ammonia in methanol (50 ml). To this was added commercially available Raney nickel slurry in water (1.8 g, 20.94 mmol) and the solution agitated under hydrogen atmosphere (45 psi) at room temp for 12 hours. The catalyst was filtered off using celite and washed with MeOH (200 ml) and the combined organics concentrated in vacuo to give 1-[1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]methanamine (16) as a clear semi-solid. MS 291 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([CH:18]([CH3:20])[CH3:19])OCC[O:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[O:14])[CH:18]([CH3:20])[CH3:19])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)C1(CCN[C@@H](C)c2ccc(Br)cc2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)C(=O)CCN[C@@H](C)c1ccc(Br)cc1
Temperature: 65 °C
Yield: 97.1 %

Procedure:
To a solution of [(S)-1-(4-bromophenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (6.5 g, 19 mmol) in MeOH (60 mL) was added concentrated aqueous HCl (60 mL). The mixture was stirred at 65° C. till the reaction was finished. The mixture was cooled to 0° C., and the pH of the mixture was adjusted to 7 by adding saturated aqueous NaHCO3. The mixture was concentrated, and the residue was extracted with EtOAc (3×100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 1-[(S)-1-(4-bromophenyl)-ethylamino]-4-methyl-pentan-3-one (5.5 g, 97%), which was used for the next step without further purification. 1H NMR (CDCl3): δ 1.07 (d, J=6.8 Hz, 6H), 1.29 (d, J=6.4 Hz, 3H), 1.89 (br, 1H), 2.54-2.62 (m, 4H), 2.66-2.69 (m, 1H), 3.68-3.72 (m, 1H), 7.18-7.20 (m, 2H), 7.41-7.44 (m, 2H).
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cccc(Br)c2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a solution of 5-nitrothiophene-2-carbonitrile (1.79 g, 11.6 mmol) and 3-bromophenol (2.00 g, 11.6 mmol) in dimethylsulfoxide (22 mL) was added potassium carbonate (1.76 g, 12.8 mmol), and the solution was stirred at 70° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 5-(3-bromophenoxy)-thiophene-2-carbonitrile (2.00 g, 62%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:31][CH2:32][CH2:33][CH3:34])[C:12]2[N:17]=[C:16]([C:18]3[CH:28]=[C:27]([CH3:29])[C:21]([O:22][CH2:23][C:24](O)=[O:25])=[C:20]([CH3:30])[CH:19]=3)[O:15][C:13]=2[N:14]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:66]1[CH2:77][CH2:76][CH2:75][C@H:67]1[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].Cl>O.CN(C)C=O>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:31][CH2:32][CH2:33][CH3:34])[C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:30])[C:21]([O:22][CH2:23][C:24]([N:66]4[CH2:77][CH2:76][CH2:75][C@H:67]4[C:68]([O:70][C:71]([CH3:73])([CH3:74])[CH3:72])=[O:69])=[O:25])=[C:27]([CH3:29])[CH:28]=3)[O:15][C:13]=2[N:14]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Reaction time: 16 h

Procedure:
82 mg of {4-[5-(trans-2-fluorocyclohexyloxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetic acid were added to 1.5 ml of N,N-dimethylformamide, and 48 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 10 mg of 1-hydroxy-7-azabenzotriazole and 195 μl of N,N-diisopropylethylamine were added, and after 5 min 24 mg of tert-butyl L-prolinate were added. After 16 h at room temperature, 10 ml of water were added, after which the mixture was adjusted to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and sodium chloride solution, dried and concentrated under reduced pressure. This gave 79 mg of the title compound.