Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
After a mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1150 mg), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-(4-fluorophenyl)-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1010 mg, yield: 93%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 178–179° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12](O)[C:13]#[C:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)[C:13]#[C:14][CH3:15]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CC#CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)OC)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 5-hydroxypyridine-2-carboxylate (1.5 g, 9.8 mmol, Molbridge) in THF (39 ml) under argon was cooled to 0° C. and 2-butyn-1-ol (1.5 ml, 20 mmol, Aldrich), triphenyl phosphine (2.95 g, 11.2 mmol, Aldrich) and diisopropyl azodicarboxylate (2.2 ml, 11.2 mmol, Aldrich) were added consecutively. The reaction mixture was stirred at room temperature for 2 h. Additional diisopropyl azodicarboxylate (1 ml) was added and the reaction mixture was stirred at room temperature for another 1 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (0% to 50% EtOAc/Hexanes) afforded the title compound as a light tan solid. MS m/z=206.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[I-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[N:1]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][NH:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCCCBr
Reactant: Nc1ccc2c(c1)C(=O)NC2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1NCc2ccc(N3CCCCC3)cc21
Temperature: 75 °C
Reaction time: 20 h

Procedure:
6-Amino-2,3-dihydro-isoindol-1-one (0.810 g, CAS 675109-45-2) was dissolved in 12 ml of acetonitrile and treated successively with sodium iodide (2.458 g, 3 eq.), 1,5-dibromopentane (1.11 ml, 1.5 eq.), and N-ethyl-diisopropylamine (2.88 ml, 3.1 eq.), and the mixture was stirred at 75° C. for 20 h. Pouring onto crushed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by crystallization from hexane/ethyl acetate yielded 6-piperidin-1-yl-2,3-dihydro-isoindol-1-one (0.669 g) as light brown crystals, MS 217.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]([C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH3:19])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:20])[C:8]2[C:9](=[C:4]([NH:3][C:12]([C:14]3[CH:18]=[CH:17][O:16][C:15]=3[CH3:19])=[O:13])[CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: Cc1occc1C(=O)N1c2ccccc2CCC1(C)C
Agent: O=S(=O)(O)O
Product: Cc1occc1C(=O)Nc1cccc2c1CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
20 ml of 85% sulfuric acid solution was added to 2.5 g (9.3 mmols) of 2,2-dimethyl-N-(2-methyl-3-furan carbonyl)- 1,2,3,4-tetrahydroquinoline under water cooling. The mixture was stirred at room temperature for 1 hour and then left standing overnight. Then, the reaction solution was poured into ice water and extracted from ethyl acetate. The resultant organic layer was sequentially washed with water, aqueous sodium hydrogen carbonate solution, water, and brine and then dried with magnesium sulfate. The dried mixture was concentrated. The concentrated residue was purified by being recrystallized with ethyl acetate/n-hexane, to obtain 2.1 g of white crystals (Compound No. 18 shown in Table 6). The yield was 84%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(OCc4ccccc4)cc3)n2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(O)cc3)n2)cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
The 2-(4-benzyloxyphenyl)-3,6-bis(4-methoxyphenyl)pyridine (3.0 g, 6.3 mmol), ammonium formate (2.0 g, 31 mmol), and 5% Pd/C (1.0 g, 0.5 mmol Pd) were combined in 150 mL of EtOH, and the reaction mixture was stirred at 50°-55 ° C. and followed by TLC (EtOAc/ Tol, 1:9). After 1 h, more ammonium formate (0.5 g, 8 mmol) was added and reaction mixture stirred at 50° C. for 30 min and no starting material remained. After cooling, the reaction mixture was filtered, concentrated, and the residue triturated with Et2O/ pet. ether. The white ppt was filtered and dried in vacuo to give 2.35g (97% yield) of product: mp 204°-205° C.; 1H NMR (CDCl3) d 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.85 (s, 1H, ArOH), 6.71-6.74 (d, 2H, J=9 Hz, ArH), 6.83-6.86 (d, 2H, J=9 Hz, ArH), 7.00-7.03 (d, 2H, J=9 Hz, ArH), 7.14-7.17 (d, 2H, J=9 Hz, ArH), 7.37-7.40 (d, 2H, J=9 Hz, ArH), 7.68-7.70 (m, 2H, ArH), 8.08-8.11 (d, 2H, J=9 Hz, ArH); MS(FD) 383(M+). Anal. Calcd for C25H21NO3 : C, 78.31; H, 5.52; N, 3.65. Found: C, 78.07; H, 5.79; N, 3.95.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
An 0° C. suspension of Example 1D (1.94 g, 8.68 mmol) in THF (44 mL) was sequentially treated dropwise with N-methylmorpholine (0.95 mL, 8.68 mmol) and 3-methylphenyl isocyanate (1.12 mL, 8.68 mmol). The mixture was stirred for 1 hour, diluted with THF (20 mL), stirred at room temperature for 3 hours, and quenched with water (20 mL). The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was suspended in 5% methanol/dichloromethane and filtered. The filter cake was washed with dichloromethane and dried to provide 2.94 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.52 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.23–7.27 (m, 1H), 7.31 (s, 1H), 7.53–7.60 (m, 5H), 7.64–7.67 (m, 2H), 8.63 (s, 1H), 8.65 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 358.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].[S:68]([CH2:82][CH2:83][C:84](ON1C(=O)CCC1=O)=[O:85])[S:69][CH2:70][CH2:71][C:72]([O:74][N:75]1[C:79](=[O:80])[CH2:78][CH2:77][C:76]1=[O:81])=[O:73].C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:80]=[C:79]1[CH2:78][CH2:77][C:76](=[O:81])[N:75]1[O:74][C:72](=[O:73])[CH2:71][CH2:70][S:69][S:68][CH2:82][CH2:83][C:84]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:85]
Reactant: O=C(CCSSCCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCNC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8 mg (10 μmol) of Intermediate 101 were dissolved in 2 ml of DMF and admixed with 8.6 mg (20 μmol) of 1,1′-{disulphanediylbis[(1-oxopropane-3,1-diyl)oxy]}dipyrrolidine-2,5-dione and 3.7 μl of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 2 h and then the solvent was evaporated off under reduced pressure and the residue was purified by preparative HPLC. 7.2 mg (68% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 4-(adamantan-1-yl)phenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide was added potassium carbonate (3.63 g, 26.29 mmol) and ethyl 4-bromobutanoate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate as a white solid (2.7 g, 90% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:22])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCc2ccccc2)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1cc(OCc2ccccc2)ccc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [4-[(phenylmethyl)oxy]-2-(trifluoromethyl)phenyl]methanol (for a preparation see Intermediate 18)(3.11 g, 11.02 mmol) in DCM (40 ml) under nitrogen in an ice-water bath was added a solution of phosphorus tribromide (1.09 ml, 11.6 mmol, Aldrich) in DCM (20 ml). The solution was allowed to warm to ambient temperature and stirred for 1.5 h. The reaction mixture was poured onto ice-water (150 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The mixture was diluted with dichloromethane (100 ml), and the phases separated. The aqueous extract was washed with dichloromethane (50 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give 4-(bromomethyl)-3-(trifluoromethyl)phenyl phenylmethyl ether as a white solid (2.96 g).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>CCO>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCC2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3-(oxiran-2-ylmethoxy)phenyl)carbamate 1.5 g, 5.66 mmol) in EtOH (30 mL) was added 1,2,3,4-tetrahydroisoquinoline 0.828 g, 6.23 mmol). The reaction mixture was heated at 100° C. for 4 h. The solvent was then removed by concentration and the residue dissolved in ethyl acetate, washed with water and the separated organic layer dried over sodium sulfate and concentrated to obtain a crude product. This product was used in next step without further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25].C(O)(=O)C>CO.[Pd]>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[CH2:23][NH:22][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)/C=C/c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CCC(=O)O)cc3)CC2)ccc1O
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A solution of (E)-3-[4-(4-oxo-piperidine-1-yl)-phenyl]-acrylic acid (which was obtained in Example 170) (0.10 g, 0.40 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methane-sulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) in methanol (15 mL) was treated with acetic acid (0.03 g, 0.5 mmol), and 0.05 g of 10% Pd/C. The mixture was hydrogenated at 25 psi for 24 h, and then filtered through Celite and evaporated. The residue was triturated with ether to give 0.18 g of an off-white solid; m.p. 130-133° C.; 1H NMR (DMSO-d6) δ 1.30-1.46 (m, 2H), 1.84-1.95 (m, 2H), 2.37-2.50 (m, 4H), 2.60-2.78 (m, 4H), 2.92 (s, 3 H), 3.53-3.62 (m, 3H), 4.46-4.55 (m, 1H), 6.85 (d, 2H), 6.92-7.10 (m, 4H), 7.18 (dd, 1H); MS (ES) m/z: 478.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][C:17]([OH:19])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:20]([NH:27][C:17](=[O:19])[CH2:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ncccc1CN1CCCCC1CC(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCCCC1CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 2-[1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidyl]acetic acid, 0.41 ml of benzylamine, 950 mg of WSC and 260 mg of HOBt were suspended in DMF, followed by stirring at room temperature for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The drying agent was filtered off, the solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1, subsequently 5:1), to give 500 mg of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([NH2:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH3:20]>C1COCC1.CCOCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:32][C:24]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH:23]=3)=[O:17])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=C=Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: CN(C)Cc1cc(N)cc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-6-(4-isocyanato-phenoxy)-pyrimidine (Stage 135.1; 594 mg; 2.40 mmol) in THF (2 ml) is mixed under a N2-atmosphere with a solution of 3-dimethylaminomethyl-5-trifluoromethyl-phenylamine (Stage 135.2; 524 mg; 2.40 mmol) in ether (10 ml). Stirring at rt affords the title compound: MS: [M+1]+=466.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[CH2:13][O:12][N:11]([CH3:14])[C:10](=[NH:15])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:17]([C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([C:8]3([CH3:16])[CH2:13][O:12][N:11]([CH3:14])[C:10](=[NH:15])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OCC(C)(c2cccc(Br)c2)NC1=N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1OCC(C)(c2cccc(-c3cccc(C#N)c3)c2)NC1=N
Yield: 44 %

Procedure:
A mixture of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R6=Me, R1=Me) (0.025 g, 0.088 mmol, 1 eq), 3-cyanophenylboronic acid (0.019 g, 0.13 mmol, 1.5 eq), FibreCat (40 mg), anhydrous ethanol (1.5 mL), and a 1N K2CO3 aqueous solution (0.12 mL, 0.12 mmol, 1.4 eq) in a microwave vial was heated in a microwave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixture was filtered, concentrated and purified by prep HPLC (B) to give 0.012 g (44%) of 5-(3-(3-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC8; R6=Me, R1=Me, R21=3-cyanophenyl) as a white solid. 1H NMR (CDCl3) 10.67 (s, 1H), 8.05 (br s, 1H), 7.85 (m, 2H), 7.50-7.66 (m, 5H), 7.35 (m, 1H), 4.22 (dd, J1=11.8 Hz, J2=48.6 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.3 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:32])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:41]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:32])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH:29]3[CH2:41][O:30]3)[CH3:31])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)CO)CC2)c2ncnn12
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3CO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-1-methylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.81 g), Dess-Martin periodinane (1.2 g) and acetonitrile (10 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added to a mixture of trimethylsulfoxonium iodide (0.39 g), sodium hydride (0.072 g) and dimethyl sulfoxide (10 mL) stirred at room temperature for 1 hr in advance, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 18%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(F)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(F)cc3)sc2c1O
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.25 mmol) and glycine (190 mg, 5.07 mmol) in 0.5 M sodium methoxide/methanol (4.0 mL) was heated at 120° C. using a CEM microwave reactor for 1H before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (50 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a brown solid (66 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.28 (br s, 1H), 9.44 (br s, 1H), 8.91 (s, 1H), 8.21 (m, 2H), 7.45 (m, 2H), 4.03 (d, J=6.2 Hz, 2H); MS: (+) m/z 348.00 (M+1).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=417.2 (M+H)+