Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:12]C(=O)N[C:9]2=[O:14])[CH:7]=1.[OH-].[Na+].NC(C1C=C(Br)C=CC=1F)(C)[C:21](O)=[O:22].S(Cl)(Cl)=O>CO>[CH3:21][O:22][C:9](=[O:14])[C:8]([NH2:12])([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:16])[CH3:15]
Reactant: CC1(c2cc(Br)ccc2F)NC(=O)NC1=O
Reactant: CC(N)(C(=O)O)c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(C)(N)c1cc(Br)ccc1F

Procedure:
The hydrolysis of the (RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 6 N sodium hydroxide solution and esterification of the resulting (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid with methanol and thionylchloride yielded the (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid methylester as a light yellow oil. The purity of the product allowed using it in the next step without further purification. Mass (calculated) C10H11BrFNO2 [276.107]; (found) [M+H]+=276, 278.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:26]=[C:27]([S:31]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[CH2:74][C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]([F:85])([F:84])[F:83])=[O:76]>CN(C=O)C>[O:76]=[C:75]([N:77]1[CH2:81][CH2:80][CH2:79][CH:78]1[C:82]([F:85])([F:83])[F:84])[CH2:74][O:38][C:37](=[O:39])[CH2:36][CH2:35][NH:34][S:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:15]3([NH:14]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:16]3)[CH2:18][CH2:19]2)=[O:24])[CH:26]=1)(=[O:32])=[O:33]
Reactant: O=C(CO)N1CCCC1C(F)(F)F
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)O)c4)CC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)OCC(=O)N5CCCC5C(F)(F)F)c4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid (step 2) (400 mg, 0.690 mmol) and N,N-diisopropylethylamine (357 mg, 2.76 mmol) in DMF (4 ml) was added HATU (262 mg, 0.690 mmol). The solution was stirred at RT for 15 min, after which time 2-hydroxy-1-(2-(trifluoromethyl)pyrrolidin-1-yl)ethanone (Int. D) (262 mg, 0.690 mmol) in DMF (2 ml) was added. The resulting solution was stirred at RT for 6 days, after which time it was poured onto water (10 ml). A white precipitate formed which was collected by filtration, and washed with iso-hexane (20 ml), and purified by C18 reverse phase chromatography eluting with MeCN/water/0.1% TFA to afford the title product; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (1H, s), 9.37 (1H, s), 9.02 (1H, s), 7.92-7.29 (4H, m), 7.24 (14N, s) 7.12 (14N,s), 6.96 (14N,s), 4.95-3.90 (11H, m), 3.66 (2H, t), 3.41 (2H, t), 3.35 (2H, m), 3.07 (2H, t) 2.20-1.61 (7H, m); LC-MS Rt 0.91 mins; 759.0 [M+H]+, Method 2minLC_v003.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH:13]=1)[C:6]([O:8]C)=O.[NH3:31]>C(O)CO>[CH3:15][N:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:31][C:6](=[O:8])[C:5]2=[CH:10][C:11]=1[N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N
Reactant: COC(=O)c1cc(N(C)c2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Solvent: OCCO
Product: CN(c1ccccc1)c1cc2c(cc1N(C)c1ccccc1)C(=O)NC2=O

Procedure:
Analogously to Example 1, 66 mg (0.16 mmol) of 4,5-bis(N-methyl-N-phenylamino)phthalic acid dimethyl ester (Example 14 A) in 5 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled, and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 358 [M+ +H], 1H-NMR (CDCl3): 3.05 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][CH:39]([CH3:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:40](=[O:41])[CH:39]([CH3:43])[CH3:38])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CC(C)C(=O)Cl
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by 2-methylpropanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 147 mg, 83%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.47-8.60 (2 H, m) 7.62-7.72 (2 H, m) 7.31 (2 H, dd, J=8.46, 5.68 Hz) 7.15 (2 H, t, J=8.97 Hz) 6.53 (1 H, s) 5.07-5.35 (2 H, m) 4.43-4.61 (0.5 H, m) 4.38 (1 H, d, J=12.88 Hz) 3.95 (3.5 H, s) 3.05-3.29 (1 H, m) 2.88-3.04 (0.5 H, m) 2.53-2.89 (4.5 H, m) 1.39-1.86 (4 H, m) 0.91-1.08 (6 H, m); m/z (APCI+) for C27H32N5O2F 478.2 (M+H)+.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1
Reactant: Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](NCc4ccccc4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cn1nnc([C@@H]2C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3N)n1
Yield: 87 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-1-phenyl-6-(2-methyl-2H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Description 33b; 357 mg, 0.77 mmol) was dissolved in ethanol (10 mL) and treated with 1,4-cyclohexadiene (5 mL), followed by 10% palladium on activated charcoal (300 mg). The suspension formed was heated at reflux for 72 hours, then cooled and filtered. The filtrate was concentrate to give the title compound as a gum (239 mg, 0.67 mmol).
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:13](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[C:14]([OH:16])=[O:15])=[O:9])([O-:3])=[O:2].[N+](=[CH:40][CH3:41])=[N-]>C1COCC1.C(OCC)C>[N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1)=[C:13](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[C:14]([O:16][CH2:40][CH3:41])=[O:15])=[O:9])([O-:3])=[O:2]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C(\COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
To a 0° C. solution of 454 mg of (2Z)-4-({[2,3-bis(nitrooxy)propoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of THF was added excess diazoethane in diethylether until crude NMR revealed complete conversion to ethyl ester. Evaporation of the solvent followed by flash chromatography of the crude residue over silica gel (30-90% EtOAc/hexane) afforded 420 mg of the title compound as a clear colourless oil. 1H NMR (500 MHz, acetone-d6): δ 7.80 (d, 2H), 7.49 (d, 2H), 7.23-7.18 (m, 3H), 7.14-7.08 (m, 2H), 5.79-5.73 (m, 1H), 5.35 (s, 2H), 5.05 (dd, 1H), 4.85 (dd, 1H), 4.64 (dd, 1H), 4.47 (dd, 1H), 4.31 (q, 2H), 3.08 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1.Br[CH2:38][CH2:39][O:40][CH3:41]>CN(C=O)C.O>[CH3:41][O:40][CH2:39][CH2:38][O:20][C:16]1[CH:15]=[C:14]([CH2:13][N:12]2[C:8]([CH3:7])=[N:9][C:10]([C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[N:11]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COCCBr
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of K2CO3 (19.9 mg, 0.144 mmol), 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 30.0 mg, 0.072 mmol) and 1-bromo-2-methoxyethane (19.9 mg, 0.144 mmol) in DMF (0.36 mL) was stirred at RT for 16 h. The mixture was diluted with H2O and extracted with 4:1 CHCl3:i-PrOH. The organic layer was separated, dried with MgSO4 and concentrated under reduced pressure. The residue was dissolved in DMSO and purified using Prep-HPLC to furnish the title compound. MS (ES+) C22H20F3N5O4 requires: 475. found 476 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.29 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.28 (m, 1H), 6.91 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (m, 1H), 5.42 (s, 2H), 4.09 (m, 2H), 3.73 (m, 2H), 3.43 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)=[CH:18][CH:17]=1.[CH2:28]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([F:44])[C:37]([F:43])=[C:38]([CH:42]=1)[C:39](O)=[O:40])(=[O:33])=[O:32])[CH3:29].CN(C=O)C>>[CH2:28]([NH:30][S:31]([C:34]1[CH:35]=[C:36]([F:44])[C:37]([F:43])=[C:38]([CH:42]=1)[C:39]([NH:27][C:25]1[S:26][C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)=[N:23][N:24]=1)=[O:40])(=[O:33])=[O:32])[CH3:29]
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Reactant: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a 20 ml scintillation vial was added EDC (54 mg, 0.283 mmol), HOAt (38 mg, 0.283 mmol) and commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (55 mg, 0.283 mmol). To this was added 5-[(ethylamino)sulfonyl]-2,3-difluorobenzoic acid as a solution in 2 ml DMF (75 mg, 0.283 mmol based on theoretical yield of preceding). The reaction mixture was stirred at room temperature overnight with a Teflon covered magnetic stir-bar. The reaction mixture was then concentrated to ˜1 ml and the residue was purified using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 30% B to 60% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-[(Ethylamino)sulfonyl]-2,3-difluoro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide as a white solid (12 mg, 19%).
Reaction SMILES: C[N:2](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][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccccn1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and pyridin-2-yl-hydrazine according to example 43 gave the desired product. MS: M=472.0 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:40]=[C:39]([C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)[O:38][N:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:40]=[C:39]([C:41]3[CH:45]=[CH:44][S:43][CH:42]=3)[O:38][N:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1noc(-c2ccsc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccsc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.23 g), potassium carbonate (0.94 g), 3-(chloromethyl)-5-(3-thienyl)-1,2,4-oxadiazole (0.75 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then 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 (0.79 g, 44%).
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCCCC.[C:15]([O-])(=[O:27])[CH2:16]CCCCCCCCCC.[CH2:29]([Sn+2]CCCC)CCC.C1CCCCC1>C1COCC1>[CH3:29][C:2]([C:1]([O:14][CH2:16][CH2:15][OH:27])=[O:13])=[CH2:3]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C=C(C)C(=O)OCCO
Temperature: 40 °C

Procedure:
A three-neck reaction flask fitted with a mechanical stirrer, condenser, dropping funnel, and thermometer was charged with 76 parts of a 32.4% THF solution of Polymer D followed by (0.25 parts) of dibutyltin dilaurate (Sigma-Aldrich) and 0.01 parts of BHT. A solution of IEM (4.77 parts) in THF (10 parts) was slowly added from the dropping funnel and the resulting solution heated at 40° C. for 30 minutes. The resulting polymer solution was cooled to room temperature, poured into a large excess of cyclohexane (approximately 5 times volume of reaction mixture), and the precipitated solid collected by filtration and dried in a 30° C. vacuum oven. The dried white solid was designated Example 2 and identified as the polymer of NIPAAM/HEMA with a plurality of the HEMA monomeric units derivatized with IEM to provide monomeric units of the following structure (Me=CH3):
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][O:25][C@H:24]1[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:24]1[C@H:23]([O:22][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:28][CH2:27][CH2:26][O:25]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.51 ml of methanesulfonyl chloride dissolved in 5 ml of benzene was added dropwise to a solution of 2.067 g of dl-7-(trans-3-hexadecyloxytetrahydropyran-2-ylmethoxy)-1-heptanol (prepared as described in Preparation 55) and 1.83 ml of triethylamine dissolved in 15 ml of benzene, whilst ice-cooling. The reaction mixture was stirred at room temperature for 15 minutes, after which it was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 2.406 g of crude dl-7-(trans-3-hexadecyloxytetrahydropyran-2-ylmethoxy)heptyl methanesulfonate as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([NH2:19])=[C:13]([CH3:20])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:1])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccccc1
Yield: 80 %

Procedure:
By using 2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 80%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: Oc1ccccc1F
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccccc3F)n2)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of compound 133 (0.3 g, 0.785 mmol), 2-fluorophenol (0.106 g, 0.942 mmol) and potassium carbonate (541 mg, 3.93 mmol) in dimethylformamide (3 mL) was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E28 as a pale yellow solid (0.2 g, 56%). mp 98-100° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 29.79 min, 99.82% purity; MS (CI): m/z 458 (M+H, 100).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[CH:1]1([NH:6][C:25]([C:12]2([CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from cyclopentylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:30]([O-])=O.[Na+]>O1CCOCC1.O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:4]=[C:3]([C:27]#[N:28])[C:2]3[N:1]=[N:30][N:8]([CH3:9])[C:7]=3[CH:6]=2)=[CH:11][C:12]=1[C:23]([F:26])([F:24])[F:25]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCOCCOC)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3-amino-6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (100 mg) was suspended in dioxane (1500 μl) and water (1500 μl) and cooled to 0° C. Hydrochloric acid (2M, 189 μl) followed by dropwise addition of sodium nitrite (25 mg) in water (500 μl) and the mixture stirred at room temperature for 2 hours. The suspension was filtered and the solid washed with water to afford pale brown solid 6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (92% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB(/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)O1.O1CCOCC1>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.O>[C:40]1(/[CH:39]=[CH:38]/[C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(Br)cc2)N1C(=O)OC(C)(C)C
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: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(/C=C/c3ccccc3)cc2)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
In a vial containing 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-bromophenyl)-1,2-pyrrolidinedicarboxylate (D78, 100 mg, 0.26 mmol), sodium carbonate (138 mg, 1.30 mmol), 4,4,5,5-tetramethyl-2-[(E)-2-phenylethenyl]-1,3,2-dioxaborolane (90 mg, 0.39 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were added dioxane (2 ml) and water (1 ml). The mixture was stirred for 2 h at 80° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered by phase separator tube and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 9:1) to afford the title compound as a light yellow solid (90 mg, 85%). Rt (HPLC): 7.02 min; MS: (ES/+) m/z: 308 (MH-Boc) C25H29NO4 requires 407.