Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:48])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:25][C:24]=3[F:47])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=O.C([Si]([O:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([O:73][CH2:74][CH:75]2[CH2:77][O:76]2)[CH:68]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:47][C:24]1[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:77][C@H:75]([OH:76])[CH2:74][O:73][C:69]3[CH:70]=[CH:71][CH:72]=[C:67]([OH:66])[CH:68]=3)=[CH:12][CH:11]=2)[CH2:19][CH2:18]1)=[O:48]
Reactant: CC(C)(C)[Si](Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNOC=O)cc3)CC2)c(F)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc(OCC2CO2)c1)(c1ccccc1)c1ccccc1
Product: O=C(NCc1ccc(O)cc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(O)c3)cc2)CC1
Yield: 18.9 %

Procedure:
[2-(4-{1-[4-(tert-Butyl-diphenyl-silanyloxy)-2-fluoro-benzylcarbamoyl]-piperidin-4-ylamino}-phenyl)-ethyl]-amino formate (1.05 g, 1.59 mmol) was reacted with tert-butyl-(3-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.642 g, 1.59 mmol) according to Procedure G to give the title compound (0.290 g, 0.3 mmol).
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[CH:17]=O)[CH2:2][CH2:3][CH3:4].[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:17]/[C:6]1[CH:7]=[C:8]([O:15][CH3:16])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C=O)cc(OC)c2ccccc12
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)OC)cc(OC)c2ccccc12

Procedure:
As in Example 111, 1-butyl-4-methoxy-2-naphthalenecarboxaldehyde (4.05 g) and (carbomethoxymethylene)triphenylphosphorane (6 g) in dichloromethane (40 mL) was stirred at room temperature for 42 hours. Crystallization of the crude reaction product from the normal work up gave 4.1 g of (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester, mp 63°-64° C. Anal. Calcd for C19H22O3 : C, 76.48; H, 7.43 Found: C, 75.89; H, 7.26
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 14.6 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (400 mg, 1.05 mmol), 4-chloropyridine hydrochloride (791 mg, 5.27 mmol), triethylamine (533 mg, 5.27 mmol), and ethanol (3 mL) yielded 70 mg (15%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.C([O:16][C:17](=O)[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21])C>C(O)(=O)C>[CH3:1][N:2]1[C:6]2[NH:7][C:17](=[O:16])[CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:5]=2[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:3]1
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Temperature: 150 °C
Yield: 24.3 %

Procedure:
A mixture of 1-methyl-3-phenyl-1H-pyrazol-5-amine (1.7 g, 9.815 mmol) and 4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (2.168 g, 11.776 mmol) in acetic acid (3.0 mL) was heated at 150° C. for 10 h in a sealed tube under constant stirring. The reaction mixture was cooled to rt and poured into rapidly stirred ice-cold water to obtain the crude product as a solid. The product was collected by filtration and dried under vacuum. The product was purified by flash-chromatography (eluent: 35% EtOAc in hexane) to yield the title compound as a white solid (0.7 g, 24%). [1H-NMR (CDCl3, 300 MHz) δ 13.65 (s, 1H), 7.52-7.37 (m, 5H), 6.78 (s, 1H), 4.20 (s, 3H); LCMS RtC=1.430 min; [M+H]+=294.0]
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:16]=2[F:25])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:26]#[N:27].[BH4-].[Na+]>CO.C(Cl)Cl.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:16]=1[F:25])[C:3](=[O:28])[NH:27][CH2:26]2)=[O:9]
Reactant: COC(=O)c1cc(Nc2ccc([Si](C)(C)C)cc2F)c(C(=O)OC)cc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2c(cc1Nc1ccc([Si](C)(C)C)cc1F)C(=O)NC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 2-cyano-5-(2-fluoro-4-trimethylsilanylphenylamino)-terephthalic acid dimethyl ester (300 mg, 0.75 mmol) in methanol (15 ml) and DCM (2 ml) at 0° C. was added silica (1 g) and cobalt (II) chloride hexahydrate (357 mg, 1.50 mmol) followed by sodium borohydride (285 mg, 7.50 mmol). During the addition of the sodium borohydride large amounts of effervescence were observed and the reaction turned black. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was filtered and the filtrate concentrated in vacuo to provide a residu that was subjected to flash chromatography (SiO2, gradient 0-20% methanol in DCM) to yield the title compound as a brown solid (138 mg, 49%). LCMS (Method B): RT=4.18 min, 2M+H−=745 (100%), M+H+=373 (25%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][CH2:14][CH3:15])(=[O:26])=[O:25]
Reactant: CCCC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-t-butoxycarbonylamino-1-hexanol (2.17 g, prepared in (1)) in dichloromethane (20 ml) were added triethylamine (1.67 ml) and methanesulfonyl chloride (0.93 ml) under ice cooling. After being stirred at the same temperature for 1 h, the mixture was washed with water, 10% aq. citric acid, sat. aq NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (Merck, Kieselgel 60) with hexane/ethyl acetate=2/1 for elution to give the product (1.32 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[C:26]4[C:34]([NH2:36])=O)=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[C:26]4[C:34]#[N:36])=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4c(C(N)=O)cc5ccccc54)ccc3o2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4c(C#N)cc5ccccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
Phosphorus oxychloride (0.14 ml) was added into N,N-dimethylformamide (0.86 ml) under ice-cooling. After 10 minutes, solution of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-2-carboxamide (0.43 g) in N,N-dimethylformamide (5 ml) was added to the solution. And then the solution was stirred for several minutes at room temperature and poured into saturated sodium hydrogen carbonate aqueous solution. The resulting precipitates were collected by filtration and washed with water and air-dried to give 4-tert-butyl-2-{5-[(2-cyanoindol-1-yl)methyl]benzofuran-2-yl}thiazol (0.43 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([OH:34])=[CH:28][CH:27]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([O:34][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:28][CH:27]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (10 mg, 0.34 mmol), (prepared as described for the starting material in Example 9), and 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, the residue was purified by chromatography, eluting with methanol/methylene chloride (1/9) followed by 2.5M ammonia in methanol/methanol/methylene chloride (5/10/85) to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (50 mg, 33%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[OH:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].[CH3:36][O:37][C:38](=[O:43])[C:39](Br)([CH3:41])[CH3:40]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([OH:19])[CH:20]4[CH2:21][CH2:22][N:23]([C:39]([CH3:41])([CH3:40])[C:38]([O:37][CH3:36])=[O:43])[CH2:24][CH2:25]4)[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCNCC3)n(C)c2n1
Reactant: COC(=O)C(C)(C)Br
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCN(C(C)(C)C(=O)OC)CC3)n(C)c2n1
Yield: 83 %

Procedure:
Following General Procedure C, (2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(piperidin-4-yl)methanol was alkylated with 2-bromo-2-methylpropionic acid methyl ester to give the racemate desired product (0.22 g, 83%). The enantiomers were separated by SFC to give 526. LCMS m/z: 289.2 (2M+H+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH3:28][C:7]1[CH:8]=[C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (340 mg, 0.76 mmol) in DMF (10 mL) was added pyrrolidine (433 mg, 6.08 mmol). Then, the reaction mixture was stirred at room temperature for 16 hours. Then, water was added and the solids were filtered. The solids were washed with water and dried to give the title compound as a white solid. Yield: 307 mg (92%). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.87 (s, 2H), 6.71 (d, J=2.0 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (m, 5H), 2.59 (t, J=6.8 Hz, 2H), 2.42 (m, 4H), 2.26 (s, 6H), 1.89 (m, 2H), 1.67 (m, 4H). MS (ES) m/z: 438.16 (M+1).
Reaction SMILES: [NH2:1][C:2](=C)/[CH:3]=[CH:4]/[C:5](/[NH:8][C:9]1[C:18]2[CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:15](=[O:28])[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1)=[CH:6]/[CH3:7].[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:18]4[CH2:17][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[C:15](=[O:28])[NH:14][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)=[O:39])=[C:33]([C:40]([F:41])([F:42])[F:43])[CH:32]=1
Reactant: O=C=Nc1ccc(F)cc1C(F)(F)F
Reactant: C=C(N)/C=C/C(=C/C)Nc1ccnc2c1CN(Cc1ccc(OC)cc1)C(=O)N2
Product: COc1ccc(CN2Cc3c(Nc4ccc(NC(=O)Nc5ccc(F)cc5C(F)(F)F)cc4)ccnc3NC2=O)cc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 63 using 5-[(Z)-4-amino-1-eth-(E)-ylidene-penta-2,4-dienylamino]-3-(4-methoxy-benzyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one and 4-fluoro-1-isocyanato-2-trifluoromethyl-benzene. LC-MS (M+H=581, obsd.=581).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:29]1[CH:44]=[CH:43][C:32]([C:33](ON2C(=O)CCC2=O)=[O:34])=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:34])=[CH:43][CH:44]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: NCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NCCS(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-[p-(2,2,2-trifluoro-N-hexadecylacetamido)benzoyloxy]succinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0M sodium hydroxide and 25 ml. of water. After stirring for 10 min., the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid, m.p. 190°-220° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[C:32]([NH:35][NH2:36])(=[O:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[C:32]([NH:35][NH:36][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])(=[O:34])[CH3:33]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Reaction time: 20 h
Yield: 56.6 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (114.5 mg, 0.257 mmol) synthesized in Example (18a) was dissolved in N,N-dimethylformamide (4 mL), acetohydrazide (39.4 mg, 0.531 mmol), HATU (150.1 mg, 0.395 mol) and N,N-diisopropylethylamine (70 μL, 0.40 mmol) were added, and stirring was carried out at room temperature for 20 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-100%) to afford the desired compound (73.0 mg, yield 57%) as a white solid.
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]([CH3:34])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH:23]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH3:34])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)c1cccs1
Reactant: CC(CCN1CCC(O)CC1)Oc1ccccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCN1CCC(OC(c2ccccc2)c2cccs2)CC1)Oc1ccccc1[N+](=O)[O-]

Procedure:
The procedure of Example 36 (a) was repeated except for using phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)-3-methylpropyl]piperidine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[CH3:14][NH:15][C:16]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:22][CH:21]=1)=[O:17]>>[CH3:14][NH:15][C:16]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:29][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:28])=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: CNC(=O)COc1ccc(CC(C)N)cc1
Product: CNC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetylthiazole and 2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethylamine, followed by reduction and purification of the base on a silica gel column using methylene chloride/methanol =9:1 as eluant.
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH2:16]([CH2:18][NH2:19])[OH:17]>O1CCOCC1>[OH:17][CH2:16][CH2:18][NH:19][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Reactant: NCCO
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1

Procedure:
A mixture consisting of 4.9 gm., 0.02 mole, of 2-(2-chloro- 5-thiadiazoly)-1-methyl-5-nitroimidazole, 3.0 gm., 0.05 mole, of ethanolamine, and 50 ml. of p-dioxane is stirred at room temperature for twenty-four hours. The precipitate is collected, washed with aqueous sodium bicarbonate solution, dried and recrystallized from methanol to give the pure compound melting at 208°-209° C. Working up the mother liquors gives additional material, the total yield being 3.4 gm.
Reaction SMILES: N[C@@H:2]([CH:11](C)[CH3:12])[C@@H:3]([C:5]1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].BrCCCCBr.BrCCCCCBr>CCOC(C)=O.CCCCCC>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:12][CH2:11][CH2:2][CH2:3][CH2:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CC(C)[C@H](N)[C@H](O)c1ccccc1
Agent: BrCCCCCBr
Solvent: CCOC(C)=O
Solvent: BrCCCCBr
Solvent: CCCCCC
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCCC1
Yield: 91 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenyl-ethanol, and replace 1,4-dibromobutane with 1,5-dibromopentane. Column chromatography (Silica gel 50 g, eluent is n-Hexane:EtOAc=5:1) is used to purify the coarse product and a white solid (1.28 g) is obtained. The yield is 91% and the other analysis includes:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]2[O:21][C@:22]3([CH2:30][N:31]=2)[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]3)=[N:17][CH:18]=1>C1COCC1>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([NH:19][C:20]2[O:21][C@:22]3([CH2:30][N:31]=2)[CH:27]2[CH2:28][CH2:29][N+:24]([O-:6])([CH2:25][CH2:26]2)[CH2:23]3)=[N:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cn1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cnc(Cl)cn3)O1)C2
Reaction time: 2 h
Yield: 94 %

Procedure:
3-Chlorobenzoperoxoic acid (104 mg, 0.466 mmol) was added to a solution of (R)—N-(5-chloropyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (114 mg, 0.388 mmol) in THF (3 mL) at room temperature and stirred for 2 h. The mixture was concentrated and the crude product was purified by flash chromatography on a 40 g silica gel cartridge with 10 to 30% [9:1 MeOH/NH4OH] in EtOAc, 30 min. Pure fractions were pooled, concentrated and dried. The residue was dissolved in EtOAC/MeOH 95:5, passed thru a 0.22 micron filter, concentrated and dried under high vacuum to yield (S)-2-(5-chloropyrazin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (113 mg, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:22][CH2:23][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
0.35 g of tert-butyl (4-{4-[5-(4-fluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.69 mmol, 1 eq.) is placed in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid (13.46 mmol, 19.6 eq.) is added and the reaction medium is stirred for 18 hours at room temperature. The solvent is evaporated off and the residue is taken up in ethyl acetate, ethanol and methanol to give 117 mg of (4-{4-[5-(4-fluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetic acid.
Reaction SMILES: CCCCCC.[CH3:7][CH:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH2:9]O.[CH2:18]([O:25]COC[C@@H](C)COS(C1C=CC(C)=CC=1)(=O)=O)[C:19]1C=CC=C[CH:20]=1>O>[CH3:7][C@@H:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])/[CH:9]=[CH:20]\[CH2:19][CH2:18][OH:25]
Reactant: CC(CO)CCCC(C)(C)O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Solvent: O
Solvent: CCCCCC
Product: C[C@H](/C=C\CCO)CCCC(C)(C)O

Procedure:
UV (hexane) λmax 234.0 (ε27 800), 241.0 (ε30 200), 248.5 (sh, ε19 900) nm; 1H NMR (400 Hz, CDCl3) δ0.86 (3H, d, J=6.5 Hz, CH—CH3), 1.21 [6H, s, C(CH3)2], 2.08 (2H, q, J=6.9 Hz, 4′-H2), 2.26 (1H, dd, J=13.1, 7.1 Hz), 2.39(1H, dd, J=13.4, 7.2 Hz), 2.56 (1H, dd, J=13.5, 4.2 Hz), 2.70 (1H, dd, J=13.3, 4.3 Hz), 4.48 (2H, m, 1- and 3-H), 5.10 (2H, s, C═CH2); 5.70 (1H, dt, J=15.0, 6.9 Hz, 3′-H 6.03 (1H, d, J=10.8 Hz, 1′-H), 6.29 (1H, dd, J=15.0, 10.8 Hz, 2′-H); MS (El) m/z (relative intensity) no M+, 318 (M+−H2O, 19), 300 (8), 285 (4), 59 (100); HRMS (ESI) exact mass calculated for C21H34O2 (M+−H2O) 318.2559, measured 318.2570.