Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([C@@:7]1([CH2:26][CH3:27])[NH:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:10]=2[S:9][CH2:8]1)[CH2:4][CH2:5][CH3:6].Cl>C(O)(=O)C>[Br:1][C:21]1[C:22]([O:24][CH3:25])=[CH:23][C:10]2[S:9][CH2:8][C@:7]([CH2:3][CH2:4][CH2:5][CH3:6])([CH2:26][CH3:27])[NH:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH:20]=1
Reactant: CCCC[C@]1(CC)CSc2cc(OC)ccc2[C@@H](c2ccccc2)N1
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: CCCC[C@]1(CC)CSc2cc(OC)c(Br)cc2[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Bromine (18.6 g) was added to a solution of the product (10.4 g) from step (f) dissolved in glacial acetic acid (150 ml). The reaction mixture was stirred at room temperature for 2 hours. Acetic acid was removed in vacuo, added another 100 ml and concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with sodium metabisulfite and 1N NaOH. The organic layer was separated, dried and concentrated in vacuo to give a brown oil which was then converted to the hydrochloride salt with ethereal HCl. This solid was filtered, washed with ether and then treated with 1N NaOH and EtOAc to get the title product (8.9 g) as an orange oil. 1H NMR consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[C:3]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([N:7]1[C@H:14]2[C@H:9]([CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13]2)[CH2:8]1)=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:14]12[N:7]([C:5]([C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[C:3]=3[N:25]3[N:29]=[CH:28][CH:27]=[N:26]3)=[O:6])[CH2:8][C@H:9]1[CH2:10][CH2:11][NH:12][CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3cccc(F)c3-n3nccn3)[C@@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(F)c1-n1nccn1)N1C[C@H]2CCNC[C@H]21
Reaction time: 3 h

Procedure:
To (1S,6R)-tert-butyl 8-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (656 mg, 1.6 mmol) in CH2Cl2 (10 mL) was added TFA (10 mL). After 3 h, the volatiles were removed via rotovap. The resulting residue was neutralized using 5% Na2CO3 (aq) and extracted with CH2Cl2 (3×). The aqueous layer was saturated with NaCl and extracted with CH2Cl2 (3×). The combined organics were dried (Na2SO4) and concentrated to give the title compound as a yellow foam that was used without further purification. MS (ESI) mass calcd. C15H16FN5O, 301.32; m/z found 302.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:8]([Cl:16])[C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:17]([CH2:26][CH:23]2[CH2:25][CH2:24]2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:8]([Cl:16])[C:9]=1[O:10][CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: BrCC1CC1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To a suspension of NaH (0.327 g, 60% in paraffin oil, 8.1 mmol) in DMF (100 mL), slowly added a mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8 mmol) and cyclopropyl methylbromide (0.718 mL, 7.5 mmol) dissolved in DMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reaction mixture was allowed stir at 0° C. for 15 min, upon which the mixture was poured onto crushed ice and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and evaporated. The residue was purified by Flash column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (2.35 g) as a thick syrup.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[CH2:52]1[O:55][CH:53]1[CH3:54]>>[OH:55][CH:53]([CH3:54])[CH2:52][NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:15]([CH3:28])([CH3:29])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:36][C:37]([CH3:51])([CH3:50])[N:38]([O:43][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:39]([CH3:41])([CH3:42])[CH2:40]2)[N:3]=1
Reactant: CC1(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: CC1CO1
Product: CC(O)CNc1nc(NCCCCC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(NCCCCC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1

Procedure:
The title compound is prepared from the reaction of the compound prepared in Example 22 with propylene oxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:21]1([O:27][CH2:28][C@@H:29]2[O:31][CH2:30]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20][CH2:30][C@@H:29]([OH:31])[CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: c1ccc(OC[C@H]2CO2)cc1
Reactant: COC(=O)c1cccc(-c2cccc(NCCN)c2)c1
Product: COC(=O)c1cccc(-c2cccc(NCCNC[C@@H](O)COc3ccccc3)c2)c1

Procedure:
Electrospray MS (positive ion): (M+H) 421.1; from methyl-3′-[(2-aminoethyl)amino]-[1,1′-biphenyl]-3-carboxylate (117 mg) and (R)-(-)-3-(phenyloxy)-1,2-epoxypropane (54 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15]>CN1CCOCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN1CCOCC1
Product: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl

Procedure:
Heat a slurry of 2-chloro-4-fluoro-3-methyl-benzonitrile (0.4 g, 2.36 mmol) and L-proline (2.11 g, 18.8 mmol) in N-methylmorpholine (1.6 mL) at 200° C. in a microwave for 30 min. Partition the reaction between 2N aqueous hydrochloric acid and ethyl acetate. Separate and extract the organic portion with 2N aqueous sodium hydroxide. Acidify the aqueous extract to pH 1 by adding concentrated hydrochloric acid and back extract into ethyl acetate. Extract the combined organic portions with brine, dry over magnesium sulphate, filter, and concentrate under reduced pressure to give the title compound. (0.395 g, 63%) mass spectrum (m/e): 263 (M−1); 1H NMR (300 MHz, CDCl3): δ 8.66 (bs, 1H0, 7.31 (d, 1H), 6.75 (d, 1H), 4.38 (t, 1H), 3.67 (m, 1H), 3.10 (m, 1H), 2.43 (m, 1H), 2.29 (s, 3H), 2.20-1.90 (m. 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=1[O:21][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: COc1cccc(CN)c1OC
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(OC)c1OC
Yield: 91 %

Procedure:
The compound prepared in Example 3 was reacted with 2,3-dimethoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 91%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([NH2:22])=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Yield: 23.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (255 mg, 1.27 mmol), D-phenylalanine amide (220 mg, 1.34 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. The mixture was then purified by HPLC to give (R)-2-(3-bromo-4-cyanophenylamino)-3-phenylpropanamide (102 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].S(Cl)(Cl)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=[CH:6][CH:7]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ncccc1CO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCc1ncccc1CN=[N+]=[N-]

Procedure:
The product of Example 124A, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 163 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].C([O-])=O.[NH4+]>CO.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of 1-chloro-4-(4-(2-nitroethyl)phenoxy)-2-(trifluoromethyl)benzene (21 g, 60.7 mmol) and ammonium formate (30.6 g, 486 mmol) in methanol (250 mL) and water (250 mL), was added zinc powder (15.89 g, 243 mmol). The reaction mixture was stirred at 80° C. for 2 h, filtered through a glass grit and washed with methanol. The filtrate was concentrated and the residue was extracted with DCM (200 mL), and then washed with sat. NaHCO3 (100 mL), brine, and dried over anhydrous Na2SO4 and concentrated. Purification via FC (DCM/CH3OH=100/8) afforded the title compound (7.0 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[F:20][C:21]([F:29])([F:28])[CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25]>O1CCCC1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:25][CH2:24][CH2:23][CH:22]([C:21]([F:29])([F:28])[F:20])[CH2:26][CH3:27])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CCO)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 96 h

Procedure:
The solution of 3-(trifluoromethyl)-1-pentanol in diethyl ether obtained in Step 4 and 26.8 g of p-toluenesulfonyl chloride were dissolved in 300 ml of tetrahydrofuran. To the solution was added dropwise 20 ml of triethylamine at room temperature, and stirred at the same temperature for 4 days. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was sequentially washed with 10% hydrochloric acid and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain 18.4 g of 3-trifluoromethyl-pentyl p-toluenesulfonate.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Br.[Cl:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1.O=[Mn]=O>[Br:6][C:7]1[N:8]=[C:9]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[C:28]1[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)c1nc(Br)c(Br)n1COCC[Si](C)(C)C
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(Br)c(-c2ccnc(Cl)n2)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooled solution of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30 minutes at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous THF (2 mL) was added dropwise and the reaction was stirred at −78° C. for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and allowed to warm to room temperature. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3×) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 hours. The reaction was allowed to cool to room temperature and filtered through Celite. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes) to give 10 g (37%) of 4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: LCMS (m/z): 445. 0 (MH+), tR=1.35 minutes. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m, 2H), 1.49 (s, 9H), 0.76 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:26])([CH3:25])[CH2:15][O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.C(O)(=O)C.C1COCC1>O>[OH:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:26])([CH3:25])[CH2:15][O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(CCCCCC(CCCCCC(C)(C)CC(=O)c1cccnc1)OC1CCCCO1)COC(=O)c1cccnc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCCCCC(O)CCCCCC(C)(C)CC(=O)c1cccnc1)COC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
Nicotinic acid 8-(tetrahydropyran-2-yloxy)-2,2,14,14-tetramethyl-15-nicotinoylpentadecyl ester (9.0 g, 14.7 mmol) was heated in a mixture of glacial acetic acid, THF, and water (160 mL/80 mL/40 mL) to 45° C. for 6 h, then stirred overnight at ambient temperature. After the reaction was completed (TLC), the reaction mixture was poured onto ice (220 g), stirred for 30-45 min and extracted with methylene chloride (4×100 mL). The combined organic layers were washed with saturated NaHCO3 solution (4×100 mL) and brine (100 mL), dried over MgSO4, and concentrated to give a crude oil (7.9 g). Purification by chromatography (silica gel, 75 g, heptanes:ethyl acetate=1:1) afforded nicotinic acid 8-hydroxy-2,2,14,14-tetramethyl-15-nicotinoylpentadecyl ester (4.5 g, 58%) as a white solid. Mp 65-67° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 9.24 (s, 2H), 8.78 (d, J=3.8 Hz, 2H), 8.31 (d, J=8.0 Hz, 2H), 7.42 (dd, J=8.0, 4.9 Hz, 2H), 4.08 (s, 4H), 3.58 (br s, 1H), 2.02 (br s, 1H, OH), 1.62-1.08 (m, 20H), 1.00 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 164.96, 153.03, 150.53, 136.81, 126.17, 123.16, 73.18, 71.58, 39.17, 37.41, 33.96, 30.44, 25.61, 24.37, 23.78. HRMS (EI, nba): Calcd for C3H47N2O5 (MH+): 527.3485. found: 527.3482. HPLC: 99.7% pure. Elemental analysis (C31H46N2O5): Calcd for C, 70.69; H, 8.80; N, 5.32. Found: C, 70.63; H, 8.83; N, 5.41.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1.[C:13]([O:17][C:18](N=[N+]=[N-])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>O1CCOCC1>[C:13]([O:17][C:18]([N:6]1[CH2:7][CH:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 73.7 %

Procedure:
A stirred mixture of 100 g (510 mmol) of 5, 75.0 mL (540 mmol) of t-butoxycarbonylazide, 150 mL of triethylamine, 500 mL of water and 500 mL of p-dioxane was heated under nitrogen to 50° C. for 15 h. The mixture was reduced in volume by one half on a rotary evaporator and extracted with four 100 mL portions of ether. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to a yellow oil under reduced pressure. Distillation of the oil under reduced pressure gave 97.5 g (69.6%) of 6 was a pale yellow oil: bp 126°-128° C. (0.05 mm); 1H NMR (CDCl3) δ1.27 (t, 3H, J=7 Hz), 1.45 (s, 9H), 1.8-2.4 (m), 3.4-3.7 (m), 4.2 (q, 2H, J=7 Hz), 4.4-4.6 (m); 13CNMR (CDCl3) δ14.2, 28.2, 28.3, 38.2, 39.0, 54.4, 57.7, 58.0, 60.9, 68.7, 69.4, 79.9, 80.1, 153.8, 154.3, 172.7, 173.0; IR (neat) 3450, 1735, 1680 cm-1. [α]D20 -68.3° C. (c=2, EtOH) (lit. [α]D20 -67.8° C. (c=1.75, EtOH).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:26][N:25]([CH2:23][CH3:24])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNN
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Product: CCc1nn(CC)c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-1,3,5-triethyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and ethylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (ISP): 323.2 ((M+H)+.).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Fc1cnc(Cl)nc1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCC(OC)CC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCC(OC)CC4)n2)CCN(c2ncc(F)cn2)C3)cc1

Procedure:
The compound was prepared following the general procedure in Example 287, substituting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-d]azepin-2-yl)phenyl)urea for 1-ethyl-3-(4-(4-(4-methoxypiperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea and substituting 4-Chloro-6-methylpyrimidine for 2-Chloro-5-fluoropyrimidine: LC-MS m/z=507 (M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O[C:22]1[C:27]([C:28]2[NH:29][C:30](=[O:47])[C:31]3[C:32](=[C:34]([CH2:44][CH2:45][CH3:46])[N:35]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[N:36]=3)[N:33]=2)=[CH:26][C:25]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:24][N:23]=1)C>>[CH2:57]([N:54]1[CH2:55][CH2:56][N:51]([S:48]([C:25]2[CH:26]=[C:27]([C:28]3[NH:29][C:30](=[O:47])[C:31]4[C:32](=[C:34]([CH2:44][CH2:45][CH3:46])[N:35]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)[N:36]=4)[N:33]=3)[C:22]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:23][CH:24]=2)(=[O:50])=[O:49])[CH2:52][CH2:53]1)[CH3:58]
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Reactant: OCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccccn3)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 100 °C
Reaction time: 14 h
Yield: 21 %

Procedure:
A stirred mixture of potassium bis(trimethylsilyl)amide (260 mg, 1.32 mmol) and 2-hydroxymethylpyridine (5 ml) was heated at 100° C. for 1 hour, then the title compound of Example 26 (150 mg, 0.26 mmol) added and the reaction mixture stirred at 100° C. for 14 hours. The resulting cool mixture was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases separated and the aqueous phase extracted with dichloromethane (2×10 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure, then the residual yellow oil purified by column chromatography on silica gel, using dichloromethane: ethyl acetate: methanol (47.5:47.5:5) as eluant, to afford the title compound (35 mg, 21%) as a white solid. δ (CDCl3): 0.94 (3H,t), 1.03 (3H,t), 1.73 (2H,m), 2.40 (2H,q), 2.55 (4H,m), 2.98 (2H,t), 3.14 (4H,m), 5.69 (2H,s), 5.92 (2H,s), 7.07 (1H,d), 7.21 (1H,m), 7.33 (2H,m), 7.62 (1H,m), 7.76 (1H,m), 8.58 (2H,m), 8.81 (1H,s), 8.85 (1H,d), 12.80 (1H,s). LRMS: m/z 630 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH:19]([CH3:23])[CH2:20][NH:21][CH3:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39](=[O:44])[CH2:40][CH2:41][CH2:42]Br>ClCCl>[CH3:37][O:38][C:39](=[O:44])[CH2:40][CH2:41][CH2:42][N:21]([CH2:20][CH:19]([O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)[CH3:23])[CH3:22]
Reactant: CNCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Reactant: COC(=O)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN(C)CC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Put 25 mg (0.064 mmol) (+/−)-2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-N-methylpropane-1-amine with 13 mg (0.128 mmol) triethylamine in 250 μl dichloromethane. Add 23.2 mg (0.128 mmol) 4-bromobutyric acid methyl ester and stir overnight at RT. Add the same amounts of triethylamine and 4-bromobutyric acid methyl ester again and stir for a further 24 h at RT. Then concentrate by evaporation and purify the residue by thick-layer chromatography on silica gel (solvent: dichloromethane/methanol 95:5). Extract the product-containing zone with dichloromethane/methanol 9:1. 22.4 mg of the target compound is obtained as raw product.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:37])[C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:38]([O:41][CH2:42][CH2:43]Br)(=[O:40])[CH3:39]>>[C:38]([O:41][CH2:42][CH2:43][N:8]([C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:37])[C:9]1[C:10]([I:36])=[C:11]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:15])(=[O:40])[CH3:39]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(C)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN(C(=O)C(C)OC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Yield: 95 %

Procedure:
5-(2-Acetoxypropionylamino)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide was alkylated with 2-bromoethyl acetate according to the general procedure described in Example 25a. After work up the product was isolated in 95% yield.