Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][C@@H:10]2[O:27][C@H:26]([CH2:28][O:29]C(=O)C)[C@@H:21]([O:22]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[C:5]=1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:3])[CH3:2].C[O-].[Na+]>O1CCCC1.CO>[CH2:41]([O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][C:5]1[C:6]([O:9][C@@H:10]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:21]([OH:22])[C@H:16]([OH:17])[C@H:11]2[OH:12])=[N:7][NH:8][C:4]=1[CH:1]([CH3:3])[CH3:2])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-benzyloxybenzyl)-5-isopropyl-1,2-dihydropyrazol-3-one (114 mg) and acetobromo-α-D-glucose (173 mg) in acetonitrile (2 mL) was added silver carbonate (127 mg), and the mixture was stirred under shading the light at room temperature for 3 days. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1) to give 5-isopropyl-4-(2-benzyloxybenzyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 5-isopropyl-4-(2-benzyloxybenzyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 50 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (22 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH:20]=[O:21])[CH2:14]2)([CH3:10])([CH3:9])[CH3:8].CI>CCOCC>[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:1])([CH:20]=[O:21])[CH2:14]2)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: CC1(C=O)Cc2ccc(C(C)(C)C)cc2C1
Yield: 6.6 %

Procedure:
To a solution of potassium tert-butoxide (Fluka, 0.45 g, 4 mmole) and of 5-tert-butyl-2-indancarbaldehyde (ex. 4; 0.71 g, 3.5 mmole), there was added at room temperature and under N2, methyl iodide (0.56 g, 4 mmole) and reaction was allowed at room temperature, under stirring. The mixture was taken in ether and washed with NH4Cl and brine, dried over Na2SO4 and concentrated (0,9 g). Chromatography on SiO2 (30 g), with toluene as eluting agent, provided 50 mg (purity>99%, yield 7%) of the desired aldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O:13][CH2:14][CH3:15])(=O)C>[Ni].C(O)C>[CH2:14]([O:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[C:15]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Agent: [Ni]
Solvent: CCO
Product: c1ccc(COc2cccc3cc[nH]c23)cc1

Procedure:
Wet Raney nickel is added in portions to a stirred refluxing solution of 7-(benzyloxy)-3-methylthio)indole (4.0 g, 14.9 mmol) in ethyl acetate (100 ml) and ethanol (60 ml) until all the starting material has been consumed (by RP HPLC). The mixture is filtered, the filtrate evaporated and the residue chromatographed on silica in ethyl acetate-hexane (1:8) to give a pale oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]#N)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(OP(OCC)OCC)C.O>CO>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Agent: CCOP(OCC)OCC
Solvent: CO
Solvent: O
Product: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A mixture of 3,5-bis(1,1-dimethylethyl)-4-hydroxyphenylthiocyanate (238 g, 0.90 mole), triethylphosphite (225 g, 1.35 mole), water (200 g), and methanol (2000 ml) was stirred at reflux for two hours. Upon cooling, the mixture was concentrated in vacuo. The residue was triturated with water, and the solid was collected by filtration and air dried. Recrystallization from aqueous methanol gave the title compound, m.p. 69°-71°.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][N:22]=3)[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[O:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH:43]1[O:42][NH:41][C:27]([C:24]1[CH:23]=[N:22][C:21]([N:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:20]=3[CH2:19]2)=[N:26][CH:25]=1)=[O:28]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a stirred solution of 2-(9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylic acid (90 mg) in DCM (5 mL) was added EDCI (74 mg) at 0° C. and the reaction mixture was stirred for 20 min. NH2OTHP (30 mg) was added and the temperature was allowed to attain room temperature. After stirring at room temperature overnight, it was diluted with DCM. The organic layer was washed with water and then concentrated under vacuum. The residue obtained was purified by column chromatography to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (60 mg, 53% yield), m/e=484 (M+1).
Reaction SMILES: C(N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55]C(NC(=O)CC2C=CC=CC=2)=S)[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=1[CH2:76][C:77]([N:79]=[C:80]=[S:81])=[O:78]>>[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=1[CH2:76][C:77]([NH:79][C:80](=[S:81])[NH:55][C:41]1[CH:42]=[CH:43][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[CH:52]=[CH:53][S:54][C:47]=23)=[C:39]([F:38])[CH:40]=1)=[O:78]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cc1c(F)cccc1F)N=C=S
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Product: O=C(Cc1c(F)cccc1F)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 23 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 2-(2,6-difluorophenyl)acetyl isothiocyanate, title compound 192c was obtained in 23% yield. Characterization of 192c is provided in table 18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.C(COC)OC>O>[C:19]([C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(-c2ccccc2N)cc(C(C)(C)C)c1O
Reactant: O=C1CCCC(=O)O1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc(-c2ccccc2NC(=O)CCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
A solution of 1.9 g (6.4 mmole) of the known compound 2'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl, 0.8 g (7.0 mmole) of glutaric anhydride and 50 ml of glyme was heated on a steam bath for three hours, then an additional 0.20 g of glutaric anhydride was added. The mixture was heated at reflux for six hours, then poured into water. The aqueous mixture was extracted with diethyl ether, and the ether extracts were then washed with 10% hydrochloric acid and water. The ether solution was extracted with dilute sodium carbonate solution, and the aqueous extracts were acidified to about pH 1 with 10% hydrochloric acid. An oil separated and crystallized after scratching to initiate crystal formation. Recrystallization of the residue from aqueous ethanol provided tan crystals of N-(3',5'-di-tertiary-butyl-4'-hydroxy-2-biphenylyl)-glutaramic acid, m.p. 132°-134° C. Anaylsis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 73.0; % H, 8.0; % N, 3.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Br)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.5 %

Procedure:
A suspension of 2-bromo-5-nitrobenzenamine (26.0 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (23.0 g) in chlorobenzene (150 ml) was heated to reflux under nitrogen and stirred for 15 hours before cooling to room temperature. The gummy mixture was diluted with dichloromethane (150 ml) and extracted with water (4×400 ml, acidified with 2N HCl). The combined aqueous extracts were basified with 2N sodium hydroxide (to pH 12) and extracted with dichloromethane (4×500 ml). The combined organic extracts were dried and concentrated in vacuo to give a brown oil which was purified by FCC eluting with System A (300:8:1 gradient to 200:8:1) to give the title compound as a brown solid (9.498 g) m.p. 100°-103° C.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20]Br>C1COCC1>[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][N:11]1[CH:12]=[CH:13][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:10]1
Reactant: COC(=O)CCBr
Reactant: CSc1nccc(-c2cc[nH]c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCn1ccc(-c2ccnc(SC)n2)c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
2-Methylsulfanyl-4-(1H-pyrrol-3-yl)-pyrimidine (260 mg, 1.36 mmol) was added to a suspension of fat free sodium hydride (39 mg, 1.63 mmol) in 5 ml of THF. The mixture was heated to 50° C. for 20 minutes. Then, 3-bromo-propionic acid methyl ester (0.156 ml, 1.36 mmol) was added and the temperature was increased to 80° C. After 14 hours, the mixture was cooled, quenched with water and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The crude product was used without further purification. Yield: 302 mg (80%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1>>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=[O:4]
Reactant: Cc1ccc(N)nc1
Reactant: O=C(Br)CBr
Product: Cc1ccc(NC(=O)CBr)nc1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 (Step 5) starting from bromoacetyl bromide and 2-amino-5-picoline.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>CS(C)=O>[Br:44][C:41]1[CH:42]=[CH:43][C:38]([O:28][C:26]2[CH:25]=[CH:24][C:22]3[NH:23][C:18]([C:3]4[C:4](=[O:17])[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]5[C:11]([C:2]=4[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=5)=[N:19][S:20](=[O:29])(=[O:30])[C:21]=3[CH:27]=2)=[N:39][CH:40]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(Oc4ccc(Br)cn4)ccc3N2)c(O)c2ccccc21
Temperature: 110 °C
Yield: 64.6 %

Procedure:
A mixture of the product of Example 321C (40.0 mg, 0.09 mmol), cesium carbonate (112 mg, 0.34 mmol), and 2,5-dibromopyridine (40.0 mg, 0.17 mmol) in dimethylsulfoxide (1.2 mL) was stirred while heating at 110° C. in a microwave reactor for 20 minutes. After cooling to 25° C., the purple mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a step gradient (0-100%) of dichloromethane in hexanes to give the title compound as an off-white solid (34.0 mg, 63%). MS (ESI−) m/z 582 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, J=6.62 Hz, 6 H) 1.93 (m, 1 H) 2.73 (m, 2 H) 6.35 (m, 1 H) 7.19 (d, J=8.82 Hz, 1 H) 7.45 (m, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.77 (m, 2 H) 7.94 (m, 2 H) 8.13 (dd, J=8.82, 2.57 Hz, 1 H) 8.19 (m, 1 H) 8.31 (d, J=2.21 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22].[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][N:12]([C:32](=[O:33])/[CH:31]=[CH:30]/[C:29]3[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=3[C:27]([F:39])([F:40])[F:26])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)CCOC(=O)NC1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a stirred solution of (±)-2-(trimethylsilyl)ethyl 7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (23 mg, 0.056 mmol), ortho-(trifluoromethyl)cinnamic acid (16 mg, 0.074 mmol) and i-Pr2NEt (0.027 mL, 0.15 mmol) in CH2Cl2 (3 mL) was added solid HATU (28 mg, 0.0.074 mmol). The mixture was stirred overnight at rt and evaporated to leave a residue which was purified by preparative HPLC to afford (±)-(E)-2-(trimethylsilyl)ethyl 7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (16.5 mg, 47%). LC-MS Method 1 tR=2.37 min, m/z=623, 625.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)[NH2:17])([O-:13])=[O:12].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[C:19]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
3-Chlorobenzoyl chloride (79 mg, 0.45 mmol, 1.05 eq), 4-dimethylaminopyridine (55 mg, 0.45 mmol, 1.05 eq) and 3-nitro-5-(pyridin-3-yloxy)aniline (0.1 g, 0.43 mmol, 1 eq) were dissolved in CH2Cl2 (5 mL) and stirred at rt for 18 h. Water was added and the organic layer separated, dried (MgSO4), filtered, and concentrated in vacuo to afford 140 mg (88%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.58 (t, J=1.9 Hz, 1H), 8.53 (d, J=2.8 Hz, 1H), 8.50 (dd, J=4.6, 1.0 Hz, 1H), 8.01 (t, J=1.8 Hz, 1H), 7.91-7.87 (m, 2H), 7.70-7.65 (m, 2H), 7.60-7.56 (m, 2H), 7.53 (dd, J=8.4, 4.7 Hz, 1H); ES-MS [M+1]+: 370.1.
Reaction SMILES: ClCCCCCS[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.[Na].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].O>CN(C)C=O>[N:16]1[CH:15]=[CH:14][N:13]2[C:8]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:20]3[C:21](=[O:23])[CH2:22][S:18][C:19]3=[O:24])=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: O=C1CSC(=O)N1
Reactant: ClCCCCCSc1cccc2nccn12
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCCCc1cccc2nccn12
Temperature: 80 °C

Procedure:
A suspension of 2.22 g (10 mmol) of 5-(5-chloropentylthio)imidazo[1,2-a]pyridine and 1.40 g (10 mmol) of thiazolidine-2,4-dione sodium salt in 30 ml of N,N-dimethylformamide was heated at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.56 g (51.4%, light brown oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].[OH-].[Na+].[CH2:14]([O:16][C:17](OCC)(OCC)OCC)[CH3:15]>C(O)C>[Cl:1][C:2]1[C:3]2[NH:4][C:17]([O:16][CH2:14][CH3:15])=[N:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CCOC(OCC)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2cccc(Cl)c2[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 35.1 %

Procedure:
2-Chloro-6-nitroaniline (3.45 g, 20.0 mmol) and stannous chloride dihydrate (18.05 g, 80.0 mmol) were heated under reflux in ethanol (80 mL) for 3 hr. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and the precipitate was filtered off. The filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was mixed with tetraethoxymethane (10 mL, 47.7 mmol) and the mixture was stirred at 130° C. for 12 hr. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give the title compound (1.38 g, 35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:34]=[C:35]([F:37])[CH:36]=1)[O:26][C@H:27]1[O:31][C:30](=[O:32])[NH:29][C@@H:28]1[CH3:33]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:29]2[C@H:28]([CH3:33])[C@@H:27]([O:26][C:25]3[CH:24]=[C:23]([F:22])[CH:36]=[C:35]([F:37])[CH:34]=3)[O:31][C:30]2=[O:32])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@@H]1Oc1cc(F)cc(F)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](Oc3cc(F)cc(F)c3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4R,5S)-5-(3,5-difluoro-phenoxy)-4-methyl-oxazolidin-2-one.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[F:47][C:48]([F:81])([F:80])[C:49]1[CH:50]=[C:51]([C:59]2[N:64]=[C:63]([CH3:65])[C:62]([C:66](N3CCC(N4CCCC4)CC3)=[O:67])=[C:61]([CH3:79])[N:60]=2)[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1.[N:82]1([CH:97]2[CH2:102][CH2:101][NH:100][CH2:99][CH2:98]2)[CH2:87][CH2:86][CH:85]([O:88]C(=O)C2C=CC=CC=2)[CH2:84][CH2:83]1>>[F:81][C:48]([F:47])([F:80])[C:49]1[CH:50]=[C:51]([C:59]2[N:60]=[C:61]([CH3:79])[C:62]([C:66]([N:100]3[CH2:99][CH2:98][CH:97]([N:82]4[CH2:83][CH2:84][CH:85]([OH:88])[CH2:86][CH2:87]4)[CH2:102][CH2:101]3)=[O:67])=[C:63]([CH3:65])[N:64]=2)[CH:52]=[C:53]([C:55]([F:56])([F:58])[F:57])[CH:54]=1
Reactant: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1
Reactant: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B, 2-(3,5-bis-trifluoromethyl-phenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid (example 15) was converted into its acid chloride, reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester (example 22) and subsequently saponified to give the title compound as colorless solid. MS: 531.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:32])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C)C(=N)N(C)C>ClCCl>[CH3:32][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]2[C:9]=1[CH:10]=[C:11]([CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:15])([F:16])[F:17])[NH:1]2
Reactant: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(F)cc21)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C#N)cc2[nH]c(CC(O)(CC3(C)CCOc4ccc(F)cc43)C(F)(F)F)cc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a chilled (0° C.) solution of 500 mg (1.1 mmol) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-(6-fluoro-4-methylchroman-4-ylmethyl)-4-hydroxypent-1-ynyl]benzonitrile in 20 mL of dichloromethane was added 460 μL (3.3 mmol) of trifluoroacetic anhydride. After 15 minutes, the reaction was concentrated in vacuo and the residue three times diluted with ether and concentrated. The resulting oil was dissolved in 1.5 mL of DMSO, and then 0.4 mL (3.2 mmol) of tetramethylguanidine was added and the mixture was warmed at 140° C. in a microwave oven. After 10 minutes, the mixture was cooled and poured onto crushed ice. The resulting solid was collected by filtration, air dried, and chromatographed on silica gel eluting with ethyl acetate-hexanes (gradient: 0-30% EtOAc) to afford two diastereomers. Further purification of the separated diastereomers by preparatory TLC (silica gel, ethyl acetate-hexanes (7:3)) gave first 82 mg (17%) of the title compound as a single diastereomer (M−1=445) and second 80 mg (17%) of the title compound as the opposite diastereomer (M−1=445).