Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:23])=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[C:24]1([CH3:36])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32](Cl)(=[O:34])=[O:33].CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:23])=[N:18][N:19]3[S:32]([C:25]3[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=3[CH3:36])(=[O:34])=[O:33])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COCOc1ccc(-c2ccc3c(C=O)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (441 mg, 1.41 mmol, 1.0 equiv) was taken up as a suspension in dichloromethane (15 mL) and was cooled to 0° C. This mixture was treated with mesitylene sulfonyl chloride (324 mg, 1.48 mmol, 1.05 equiv) and dimethylamino pyridine (DMAP) (181 mg, 1.48 mmol, 1.05 equiv). The mixture was allowed to stir for 1 h at 0° C. and was quenched with the addition of water. The mixture was partitioned between water and a 1:1 ethyl acetate/hexane organic layer. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude material which was purified by silica gel chromatography (50 mL silica, 3:7 ethyl acetate/hexane) to give 6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole-3-carbaldehyde (374 mg, 54%): Rf sm 0.17, p 0.53 (ethyl acetate-hexane 4:6); 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.41 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.73 (dd, 1H, J=1.4, 8.4 Hz), 7.3 (m, 3H), 7.08 (s, 2H), 5.36 (s, 2H), 4.08 (s, 3H), 3.71 (s, 3H), 2.74 (s, 6H), 2.40 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>>[CH2:17]([O:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: Fc1ccc(Br)cc1
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
Using the procedure of Example 551, 4-bromofluorobenzene (1.75 g, 10 mmol) was metallated and coupled with ethyl 4-bromobenzoate (2.28 g, 10 mmol) to give the title compound after chromatography (ethyl acetate-hexanes (1:9) (0.7 g)): 1H-NMR (CDCl3, 300 MHz): 8.1 (d, 2H, J=8), 7.65-7.5 (m, 4H), 7.15 (t, 2H, J=8), 4.4 (q, 2H, J=7), 1.4 (t, 3H, J=7); MS:244.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]([NH2:29])([CH3:28])[CH3:27]>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:29][CH:26]([CH3:28])[CH3:27])[S:8]1(=[O:25])=[O:24]
Reactant: CC(C)N
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Solvent: CO
Product: CC(C)NCCOCCN1c2ccccc2N(c2c(F)cccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with isopropylamine (0.8 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)propan-2-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.32 g, 31%). HRMS: calcd for C19H23F2N3O3S+H+, 412.15009; found (ESI, [M+H]+Obs'd), 412.1497.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[C:9]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]([CH3:24])[N:15]([CH3:25])[C:14]1=[O:26])(=[O:12])[CH:10]=[CH2:11].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][N:15]1[CH:16]([CH3:24])[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]([C:9](=[O:12])/[CH:10]=[CH:11]/[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=2)[C:14]1=[O:26]
Reactant: C=CC(=O)N1C(=O)N(C)C(C)C1c1ccccc1
Reactant: Fc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(c2ccccc2)N(C(=O)/C=C/c2cccc(F)c2)C(=O)N1C
Temperature: 110 °C
Yield: 76 %

Procedure:
A solution of 1-bromo-3-fluorobenzene (525 mg, 3 mmole), (4 R, 5 S)-1-acryloyl-3,4-dimethyl-5-phenylimidazolidin-2-one (500 mg, 2 mmole), Pd(OAc)2 (22 mg, 0.10 mmole), P(o-tolyl)3 (61 mg, 0.20 mmole), and (i-Pr)2NEt (0.73 mL, 4.2 mmole) in dry DMF (10 mL) was degassed (3×vacuum/N2 purge) then heated to 110° C. After 2 hr the mixture was cooled and poured into EtOAc. The resulting mixture was washed with H2O (3×), and the combined aqueous layers were back-extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered through a plug of silica gel, and concentrated. The residue was taken up in 1:1 Et2O/hexanes (10 mL) and cooled at −20° C. overnight. The solid was collected and dried in vacuo to afford the title compound (514 mg, 76%): 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=15.9 Hz, 1 H), 7.64 (d, J=15.9 Hz, 1 H), 7.15-7.45 (m, 8 H), 6.98-7.10 (m, 1 H), 5.42 (d, J=8.5 Hz, 1 H), 3.88-4.03 (m, 1 H), 2.88 (s, 3 H), 0.85 (d, J=6.6 Hz, 3 H); MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9]OC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[OH-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][N:26]=[N+:27]=[N-:28])[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (27.2 g, 99.9 mmol) was added water (500 ml) and sodium bicarbonate (9.3 g, 111 mmol); the pH of the mixture was adjusted to 6.5 with 10% sodium hydroxide solution. Sodium azide (13.1 g, 201 mmol) was added to the mixture followed by acetone (350 ml). The mixture was heated at 60° C. for 6h and left stirring at room temperature overnight. Acetone was removed under reduced pressure and the mixture was cooled in an ice-bath, acidified with concentrated hydrochloric acid to pH 3.5; the precipitated solid was filtered off, dried overnight over P205 to give 14.3 g (56%) of 7β-amino-3-azidomethyl-3-cephem-4-carboxylic acid. IR (Nujol) max 2095, 1796, 1732 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Br:13]Br.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:13][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc2c(Br)c(F)ccc2n1

Procedure:
In step (1) of the reaction scheme, the known compound 6-fluoroquinaldine of Formula II is brominated with liquid bromine in the presence of aluminum chloride in a suitable solvent such as 1,2-dichoroethane. The reaction mixture is heated at reflux for several hours to provide the novel intermediate 5-bromo-6-fluoroquinaldine of Formula III.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][NH:9]1.F[C:20](F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][N:9]1[CH3:20]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2Cl)c1=O
Product: CCOC(=O)c1cn(C)n(-c2ccccc2Cl)c1=O
Yield: 81 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2-chlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.4 g, 12 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (2.8 g, 81%) was obtained as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7]1.[Br:21]C1CC(=O)NC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:21][C:5]1[S:1][C:2]([C:6]2([C:10]3[N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]4=[N:12][N:11]=3)[CH2:7][CH2:8][CH2:9]2)=[CH:3][CH:4]=1
Reactant: c1csc(C2(c3nnc4n3CCCCCC4)CCC2)c1
Reactant: O=C1CC(Br)C(=O)N1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(C2(c3nnc4n3CCCCCC4)CCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
3-[1-(2-Thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (60 mg) was dissolved in acetic acid (3 ml) and then bromosuccinimide (38 mg) was added, followed by stirring at room temperature for 8 hours under light-shielding. The reaction solution was diluted with chloroform (30 ml) and then washed with water (10 ml), a 1M aqueous sodium hydroxide solution (10 ml), and brine (10 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 60 mg of 3-[1-(5-bromo-2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:14][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Chloroethyl chloroformate (10.0 g, 69.9 mmol) and 1-hexanol (6.5 g, 63.6 mmol) were dissolved in chloroform (80 ml) at 0° C. Pyridine (5.5 g, 69.5 mmol) was added dropwise during 17 minutes maintaining the temperature below 10° C. After stirring at room temperature for 20 hours the organic phase was washed three times with 1 normal hydrochloric acid, once with a saturated sodium hydrogen carbonate solution and finally twice with water. The organic solution was dried with magnesium sulfate and the solvent was removed at reduced pressure. The residue (11.6 g) was distilled in vacuo (Bp. 61°-72° C., 3×10-3 mbar). Yield: 9.0 g. 1H-NMR (CDCl3): delta=0.89 (CH2CH3); 1.28-1.40 (CH2CH2CH×2CH3); 1.69 (OCH2CH2); 1.83 (CH3CH); 4.20 (OCH2); 6.43 ppm (CH).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45]/[CH:46]=[CH:47]\[CH2:48][CH2:49][CH2:50][CH3:51].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:43][C:14]([F:13])([C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48][CH2:49][CH2:50][CH3:51])=[CH:30][CH:31]=2)=[N:22][CH:21]=1
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Reactant: CCCC/C=C\CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C\CCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mmol) in THF (20 ml) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.858 g, 1.50 mmol), cis-3-octene-1-ol (0.192 g, 1.50 mmol) and triphenylphosphine (0.939 g, 1.50 mmol) in THF (30 ml) and the reaction mixture stirred at room temperature for 24 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].[CH3:7][C:8]1[O:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH:15]=[O:16])[C:10](=[O:19])[C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:7][C:8]1[O:13][CH2:12][N:11]([C:14]([CH3:17])([CH:15]([OH:16])[CH2:5][CH2:4][CH:3]=[CH2:2])[CH3:18])[C:10](=[O:19])[C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CCCBr
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: -5 °C
Reaction time: 18 h
Yield: 145.5 %

Procedure:
4-Bromobut-1-ene (approximately 0.2 g) was added to a suspension of magnesium (0.17 g) in tetrahydrofuran, under an inert atmosphere at 20° C. Once the reaction had initiated, further 4-bromobut-1-ene (approximately 0.67 g) in tetrahydrofuran was added over 10 minutes. After refluxing for 1 hour, the mixture was cooled to -5° C. and a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (1.00 g) in tetrahydrofuran was added over 20 minutes. After stirring for 18 hours, ammonium chloride and ethyl acetate were added and the organic phase washed (brine), dried (magnesium sulphate) and evaporated to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylhept-6-en-3-ol (0.68 g) as a white solid, m.p. 74-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[N:6][CH:7]=1.CN1CCOCC1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH:11][C:21](=[O:22])[CH2:20][Cl:19])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: NNC(=O)c1cncc(Br)c1
Reactant: O=C(Cl)CCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
To an ice-cold suspension of 5-bromo-3-pyridinecarbohydrazide (3.0 g, 13.88 mmol) in anhydrous CH2Cl2 (60 mL) was added 4-methyl-morpholine (2.1 g, 20.82 mmol), followed by dropwise addition of chloroacetyl chloride (1.88 g, 16.67 mmol). The cold bath was then removed and the mixture stirred at rt for 15 h. Heavy precipitation occurred and the mixture was diluted with additional CH2Cl2 (50 mL) and stirring continued for 24 h. The solids were collected by filtration and washed with CH2Cl2 to afford the title compound (3.66 g, 90% yield): MS (ES) m/z 292 and 294 (M+1 Br isotopes).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Cc2ccc(O)cc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The solution of 3.26 of 6-methoxy-2-oxindole in 60 mL of dischloromethane was cooled at −3° C. and 10 mL of 1 M boron tribromide solution in dichloromethane was added dropwise. The reaction mixture was stirred in ice-bath for 1 hour, room temperature for 1 hour, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and dried in a vacuum oven overnight to give 2.56 g of the 6-hydroxy-2-oxindole (86% yield),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:18][C:19]1[N:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[N:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N:23]4[C:19]([CH3:18])=[N:20][CH:21]=[N:22]4)=[CH:32][CH:31]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=3.79 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:17])=[CH:8][C:9]=2[NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])[N:4]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:3]=1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:17])=[CH:8][C:9]=2[NH:11][CH:12]([CH2:13][O:14][CH3:29])[CH2:15][CH3:16])[N:4]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:3]=1
Reactant: CCC(CO)Nc1cc(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(COC)Nc1cc(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C
Reaction time: 0.05 h

Procedure:
A solution of 2-[3,6dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-butan-1-ol (69 mg, 0.196 mmol) in 1 ml of dry tetrahydrofuran was treated with 60% sodium hydride oil (28 mg, 0.7 mmol). After stirring for 3 minutes, methyliodide (0.3 ml) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was quenched with water and extracted with ether. The organic layer was washed with water, dried and concentrated to give 61 mg of crude material. The residue was purified through silica gel column chromatography using chloroform as eluent to give 43 mg of the title compound in yellow glass form. 1H NMR (CDCl3): 6.91 (s, 2H), 6.00 (s, 1H), 5.05 (d, 1H), 3.4-3.6 (m, 2h), 3.41 (s, 3H), 2.66 (s, 3H), 2.28 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.6-1.8 (m, 2H), 1.05 (t, 3H), ppm; IR (CHCl3) 2920, 1586 cm−1; High MS calc. 366.2413, found 3.66.24516. The glass form was converted to the corresponding HCl salt form as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][CH2:15][C@H:16]1[C@H:23]([O:24]C(=O)C2C=CC=CC=2)[CH2:22][C@H:21]2[C@@H:17]1[CH2:18][C:19](=[O:33])[O:20]2)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].Cl>CO>[Si:7]([O:14][CH2:15][C@H:16]1[C@H:23]([OH:24])[CH2:22][C@H:21]2[C@@H:17]1[CH2:18][C:19](=[O:33])[O:20]2)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Reaction time: 3 h
Yield: 76.4 %

Procedure:
1.845 g of anhydrous potassium carbonate is introduced into a solution of 11.716 g of the silyl ether produced in Example 1 in 122 ml of absolute MeOH, and the mixture is agitated under argon for 3 hours. The reaction solution is then cooled in an ice bath and gently combined dropwise with 1.86 ml of concentrated hydrochloric acid. Excess methanol is extensively concentrated under vacuum at room temperature, the residue is combined with 300 ml of methylene chloride, and the solution is dried over magnesium sulfate, filtered off, and concentrated. The oily residue is made to crystallize by trituration with hexane, thus obtaining 6.562 g of the title compound, mp 60.7° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.[F:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][N:34]=3)[C:28](OC)=[O:29])[C:21]2=[O:35])=[CH:17][CH:16]=1>>[CH:9]1([CH2:12][NH:13][C:28](=[O:29])[C:27]2[CH:32]=[CH:33][N:34]=[C:25]([N:22]3[CH2:23][CH2:24][N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:37][CH:36]=4)[C:21]3=[O:35])[CH:26]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCC1CC1
Solvent: NCc1ccccc1
Product: O=C(NCC1CC1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 54 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with cyclopropylmethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, N-(cyclopropylmethyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 54% yield: mp 135-137° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.29-7.24 (m, 2H), 7.05-6.99 (m, 2H), 6.50 (br s, 1H), 4.45 (s, 2H), 4.07-4.02 (m, 2H), 3.46-3.26 (m, 4H), 1.08-0.97 (m, 1H), 0.56-0.50 (m, 2H), 0.28-0.23 (m, 2H); MS (ES+) m/z 369.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
148 (510 mg, 1.7 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (82 mg, 3.4 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C[Si]([C:15]([F:18])([F:17])[F:16])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:15]([F:18])([F:17])[F:16])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
To a 0° C. solution of 4-bromo-2-fluorobenzaldehyde (1.00 g, 4.93 mmol) in tetrahydrofuran (50 mL) was added trimethylsilyl trifluoromethane (0.77 mL, 4.9 mmol) dropwise over 5 minutes. The reaction was stirred at 0° C. for 10 minutes. Then tetrabutylammonium fluoride (0.49 mL, 0.49 mmol, 1 M in tetrahydrofuran) was slowly added and the reaction was allowed to gradually warm to room temperature and stir for 3 days. The reaction was concentrated and the residue was taken up in dichloromethane. The solution was washed once with 1 N aqueous hydrochloric acid and once with brine. The organics were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (1.0 g, 75%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.48 (d, J=7.61 Hz, 1H), 7.39 (d, J=1.76 Hz, 1H), 7.29 (dd, J=9.56, 1.95 Hz, 1H), 5.33-5.40 (m, 1H), 2.70 (d, J=5.46 Hz, 1H).
Reaction SMILES: CS(O[C@@H:6]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[N:34]([C@H:6]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC[C@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-]
Temperature: 100 °C

Procedure:
A mixture of (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-yl methanesulfonate (1 eq) and NaN3 (5 eq) in DMF (0.5 M) was stirred at 100° C. over night. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-15% EtOAc/Hex to give (R)-(2-azido-3-(hexadecyloxy)propoxy)(tert-butyl)dimethylsilane as acolorless oil.