Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].O.[NH2:37][NH2:38].O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:37][NH2:38])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)(=[O:19])=[O:18])[C:3]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 20 °C
Reaction time: 17.5 h
Yield: 102.9 %

Procedure:
20 g (39 mmol) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano-pyridine-4-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide were suspended in 100 ml of N,N-dimethyl formamide and 7.6 ml (156 mmol) of hydrazine hydrate were added within 15 min. The reaction mixture was allowed to warm up slowly to 20° C. After 17.5 hr, at a temperature of 15° C., 250 ml of de-ionized water were added followed by slow addition of 10.5 ml acetic acid (until pH=5.4). The resulting suspension was stirred for 2 hr at 20° C. and then for additional 2 hr 0° C. The solid was filtered off under suction, firstly washed with 200 ml of de-ionized water and thereafter with 100 ml of t-butylmethylether. The residue was dried at 40° C., 2000 Pa for 18 hr. There were obtained 21.7 g (102% of theory) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide with a HPLC purity of 81.4% (w/w).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[N:15]2[N:16]=[C:17]([CH2:19][CH3:20])[CH:18]=[C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1.O>C(#N)C>[Br:9][C:10]1[N:15]2[N:16]=[C:17]([CH2:19][CH3:20])[C:18]([N+:7]([O-:8])=[O:6])=[C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1
Reactant: O=[N+]=O
Reactant: CCc1cc2c(OC)ccc(Br)n2n1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CCc1nn2c(Br)ccc(OC)c2c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
After adding nitronium tetrafluoroborate (176 mg) to a solution of 7-bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (282 mg) in acetonitrile (20 mL) at 0° C., the mixture was stirred for 20 minutes. Upon completion of the reaction, water was added, extraction was performed with ethyl acetate, the extract washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (159 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5](Cl)[N:6]=1.[I-:11].[Na+].O>CC(C)=O>[Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([I:11])[N:6]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1sc(Cl)nc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 25.8 %

Procedure:
39.8 g (0.2 mol) of 2,4-dichloro-5-nitrothiazole are dissolved in 500 ml of acetone and, after addition of 90 g (0.6 mol) of sodium iodide, the mixture is stirred at room temperature for about 6 days, the progress of the reaction being monitored by gas chromatography. The solvent is then stripped off in vacuo and the residue is stirred into water, filtered off, washed with water and dried. A substance mixture which, according to analysis by gas chromatography, contains 71.5% of 2-iodo-4-chloro-5-nitrothiazole and 25.8% of 2-chloro-4-iodo-5-nitrothiazole is obtained. HPLC (=high pressure liquid chromatography) chromatographic separation gave the pure substances with the following melting points:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:18][C:19]=2[CH2:20][CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])=[CH:32][CH:31]=1.C(N(CC)CC)C>CO.COC(OC)OC.C(Cl)Cl>[CH2:20]([C:19]1[S:18][C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:16][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:38](/[CH3:39])=[CH:37]\[C:36](=[O:41])[C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:42])[F:43])=[CH:31][CH:32]=2)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CCc1sc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: COC(OC)OC
Solvent: CO
Solvent: ClCCl
Product: CCc1sc(-c2ccccc2)nc1COc1ccc(C[C@H](N/C(C)=C\C(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 1.35 g (2.72 mmol) of Intermediate 62, 630 mg (2.72 mmol) of Intermediate 24, and 0.8 mL triethylamine in MeOH (20 mL) and trimethylorthoformate (5 mL) to yield 1.04 g (65% yield) of Example 70 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH, 4/1): Rf=0.45; 1H NMR (DMSO-d6, 300 MHz) δ11.57 (d, 1H, J=8.7), 7.96 (d, 2H, J=8.4), 7.85 (m, 2H), 7.71 (d, 2H, J=8.4), 7.44 (m, 3H), 6.92 (d, 2H, J=8.4), 5.6 (s, 1H), 5.05 (s, 2H), 4.21-4.27 (m, 1H), 3.27-3.22 (m, 1H), 2.89-2.81 (m, 4H), 1.72 (s, 3H), 1.19 (t, 3H, J=7.5); low resolution MS (ES+)m/e 594.96 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:35]([O:37][CH2:38]Cl)[CH3:36]>C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][N:22]([CH2:38][O:37][CH2:35][CH3:36])[C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Reactant: CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a stirring solution of (R)-3-(5-acetoxyhexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (3.5 g, 10.0 mmol) and diisopropylethylamine (10.32 g, 80 mmol) in chloroform (100 ml) was added chloromethyl ethyl ether (3.78 g, 40 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to provide (R)-3-(5-acetoxyhexyl)-7,8-dihydro-8-ethoxymethyl-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (2.0 g, 49% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C[Al](C)C.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[N:55][C:56]#[N:57])OC2C=CC=CC=2)=[CH:42][CH:41]=1>ClCCl.C1(C)C=CC=CC=1>[C:56]([N:55]=[C:47]([NH:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=1)[N:15]1[CH2:14][CH2:13][N:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([Cl:8])[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16]1)#[N:57]
Reactant: COc1ccc(NC(=NC#N)Oc2ccccc2)cc1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=NC#N)N2CCn3c(c(C(N)=O)c(Cl)c3-c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry dichloromethane (2 mL) under a blanket of nitrogen was treated with dry triethylamine (35 μL), then with a 2M solution of trimethylaluminum in toluene (0.30 mL) dropwise. After stirring at room temperature for a further 30 minutes the reaction mixture was treated with N-4-methoxyphenyl-N′-cyano-O-phenylisourea (64 mg, Reference Example 46) and then further stirred at room temperature for 3 hours. The reaction mixture was then heated overnight at 50° C. and then allowed to cool to room temperature. The reaction mixture was further treated with dichloromethane and then washed with a 0.5M aqueous solution of sodium carbonate. The organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of pentane and ethyl acetate (1:1, v/v) then ethyl acetate to give 2-[(cyanoimino)(4-methoxyphenylamino)methyl]-7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (10 mg) as a white solid, m.p. 170° C. MS: 451 [MH]+, 449 [MH]+.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]C1C=CC(C(=O)C)=CC=1>CCOC(C)=O>[CH3:14][C:4]1[CH:3]=[CH:2][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:6][CH:5]=1
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 4′-methylacetophenone and 2.9 mL of EtOAc to yield 1.68 grams of Intermediate 27: TLC analysis: Rf=0.61 (5/1, hexanes/EtOAc), 1H NMR (400 MHz, CDCl3, enol form) δ7.72 (d, 2H, J=8.2), 7.24 (d, 2H, J=7.4), 6.15 (s, 1H), 2.4 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: COC[O:4][CH2:5][C@@H:6]1[C:10]([C:11]([O:13][C:14](C)(C)C)=[O:12])=[CH:9][CH2:8][N:7]1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].Cl.CO.N1C(C)=CC=CC=1C.[Si:35](OS(C(F)(F)F)(=O)=O)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C[Si](C=[N+]=[N-])(C)C.CCCCCC.Cl>CO.C1(C)C=CC=CC=1>[Si:35]([O:4][CH2:5][C@@H:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH2:8][N:7]1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)[C@H]1COCOC
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CC=C(C(=O)OC)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 1-allyl 3-tert-butyl (2S)-2-[(methoxymethoxy)methyl]-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (296 mg, 0.90 mmol) in methanol (2 ml) was added hydrochloric acid/methanol(5 ml) and the mixture was stirred overnight. To the solution was added toluene and the solvent was removed in vacuo. To the residue were added methanol and toluene and the solvent was again removed in vacuo. The residue was dissolved in THF (8 ml) and thereto were added at 0–5° C. 2,6-lutidine (0.84 ml, 7.2 mmol) and tert-butyldimethylsilyltriflate (0.83 ml, 3.6 mmol). The mixture was stirred at room temperature for 1 hour and thereto was added at 0–5° C. a solution of trimethylsilyldiazomethane in hexane (2M, 0.45 ml, 0.90 mmol). Thirty minutes later the mixture was raised to room temperature and stirred for 30 minutes. Thirty minutes later to the mixture were added 1N hydrochloric acid and a saturated aqueous sodium chloride solution, and the mixture was separated with a separating funnel. The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified with silica gel (26 g) chromatography (hexane/ethyl acetate=1/5) to give 1-allyl 3-methyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (71 mg, 22%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:16]1[CH:21]=[C:20]([N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]2[N:39]=[CH:40][CH:41]=[C:18]2[N:17]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:36][Si:35]([CH3:38])([CH3:37])[CH2:34][CH2:33][O:32][CH2:31][N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:20]1[N:19]2[N:39]=[CH:40][CH:41]=[C:18]2[N:17]=[C:16]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH:21]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 876.9 %

Procedure:
The compound methyl 2-(4-hydroxyphenyl)acetate (330 mg, 0.2 mmol) was dissolved in dry DMF (3 mL) and NaH (80 mg, 60% in oil, 0.2 mmol) was added and the mixture was stirred at room temperature for 5 min. Then, 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (430 mg, 0.1 mmol) was added and the resulting mixture was heated up to 130° C. with microwave and stirred for 30 min. After cooling to room temperature, NH4Cl (aq) was added to quench the reaction and extracted with EtOAc (50 mL×3). The combined organics were washed with water and brine and dried over Na2SO4. After concentration, the residue was purified with column (silica gel, 20% EtOAc/Hexane) gave the product, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate, (490 mg) as clear oil. HPLC-MS tR=2.77 min (UV254 nm); mass calculated for formula C27H42N4O5Si2 558.3, observed LCMS m/z 559.3 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CS(C)=O>[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([CH3:13])[CH:4]=2)=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(COc2ccc(NC(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
The mixture of 4-chloromethyl-2-methylquinoline (6.84 g, 30.0 mmol), (4-hydroxyphenyl)carbamic acid tert-butyl ester (6.24 g, 30.0 mmol), Cs2CO3 (20.0 g, 60.0 mmol), and n-Bu4NI (11.1 g, 30.0 mmol) in DMSO (150 mL) was stirred at 80° C. for 3 h. The mixture was then cooled, dumped into cold water, and extracted with ethyl acetate. The combined extract was washed with water, brine, dried and concentrated. Chromatograph by CH2Cl2/EtOAc to provide compound [4-(2-methylquinolin-4-ylmethoxy)phenyl]-carbamic acid tert-butyl ester (8.0 g). ESI (M+H)+365.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=C)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].I([O-])(=O)(=O)=[O:39].[Na+]>C1COCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:39])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (1.12 g, 1.995 mmol) and sodium periodate (1.280 g, 5.98 mmol) in THF (20 ml) and Water (10 ml) was added osmium tetroxide (2.5 wt % 2-butanol) (0.501 ml, 0.040 mmol) and the reaction mixture was stirred at rt for 5 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (930 mg, 1.650 mmol, 83% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.94 (s, 1H), 8.71 (d, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H), 7.34-7.47 (m, 2H), 5.59 (s, 2H), 4.47-4.70 (m, 2H), 3.50 (t, 2H), 0.83 (t, 2H), −0.05 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[F:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:19][C:18]=1[F:24]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Yield: 70.9 %

Procedure:
Using the same reaction conditions as in Example 15, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 295 mg, 1.65 mmol) was reacted with 4-bromo-2-fluoro-benzoic acid methyl ester (350 mg, 1.5 mmol), 1,4-dioxane (25 mL), copper iodide (32 mg, 0.165 mmol), trans-1,2-diamino cyclohexane (70 mg, 0.495 mmol) and potassium phosphate (875 mg, 4.12 mmol). The resulting mixture was refluxed for 18 hours. The reaction workup afforded 350 mg of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (68.7% yield).
Reaction SMILES: ClC(OCC1C=CC=CC=1)=[O:3].[CH3:12][O:13][C:14](=[O:32])[C@@H:15]([N:17]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:18][C:19](C)=[CH2:20])[CH3:16].COC(=O)[C@@H](N(C(OCC1C=CC=CC=1)=O)CC(C)C)C.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH3:12][O:13][C:14](=[O:32])[C@@H:15]([N:17]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:18][C:19](=[O:3])[CH3:20])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C(C)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: COC(=O)[C@H](C)N(CC(C)C)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@H](C)N(CC(C)=O)C(=O)OCc1ccccc1
Yield: 14 %

Procedure:
To a solution of L-alanine methyl ester hydrochloride (6.00 g, 43.0 mmol) in MeOH (120 mL) were added at 0° C. methacrolein (4.12 g, 56 mmol), magnesium sulfate (46.6 g, 387 mmol), and sodium cyanoborohydride (3.70 g, 56 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0° C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford a 1:1 mixture of (S)-2-(2-methyl-allylamino)-propionic acid methyl ester and (S)-2-isobutylamino-propionic acid methyl ester title compound (5.4 g). This was reacted with benzyl chloroformate in analogy with intermediate 1B, leading to a mixture of (S)-2-[benzyloxycarbonyl-(2-methyl-allyl)-amino]-propionic acid methyl ester and (S)-2-(benzyloxycarbonyl-isobutyl-amino)-propionic acid methyl ester (9.8 g). This was suspended in acetone (60 mL) and water (60 mL), then sodium periodate (13.8 g, 64 mmol) and osmium tetroxide solution (2.5% in tert-butylalcohol, 2.2 mL, 0.43 mmol) were added at 0° C. The ice bath was removed, then after 16 h the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (1.88 g, 14%). Colourless oil, MS: 294.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([C:16](OC(C)(C)C)=O)[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=[C:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.C(N(CC)CC)C.[BH3-]C#N.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(=O)C>[CH2:1]([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=[C:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C(=O)OC(C)(C)C)CC2N(C)Cc1ccccc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2n(c(=O)c1O)CCN(C)CC2N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-tert-butyl 2-methyl 10-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,9,10-tetrahydropyrimido[1,2-d][1,4]diazepine-2,8(4H)-dicarboxylate (prepared as described in Example 11, Step 1-4) was taken in CH2Cl2/TFA (8/2 v/v) and stirred at room temperature for 1 hour. Volatiles were evaporated and residue was triturated with diethyl ether. MS (ES) C18H22N4O4 requires 358. Found: 359 (M+H+). The crude organic product was dissolved in MeOH and treated with formaldehyde (3 eq.) and triethylamine (3 eq.). Acetic acid was added until pH=5.5, followed by NaCNBH3 (2 eq.), and resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated to a residue which was purified on Cation Exchange Resin (Varian Mega Bond Elute SCX). After washing with MeOH, the product was collected eluting with 2N NH3 solution in MeOH. The fractions containing the desired material were concentrated under reduced pressure to yield the title compound as a yellow oil. MS (ES) C19H24N4O4 requires 372. Found: 373 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][OH:22].Cl[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][O:22][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: Cn1c(CO)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CCOP(=O)(CCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1nc(-c2ccccc2)c(-c2ccncc2)n1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 80% NaH in mineral oil (0.013 g, 0.452 mmol) in DMF at 0° C. was added 1-methyl-2-hydroxymethyl-4-phenyl-5-[4-pyridinyl]imidazole (0.100 g, 0.377 mmol) in DMF. The resulting bright yellow solution was stirred at 0° C. for 0.5 h when diethyl chloromethylphosphonate (0.070 mL, 0.452 mmol) dissolved in 0.079 mL, of HMPA was added. The resulting mixture was stirred at 0° C. for 15 min and then warmed to rt. After 5 h, the solution was partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2 /MeOH. The title compound was obtained as a light amber oil (0.088 g, 56%): ESMS (m/z): 416 (M+ +H).