Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.NN.FC1C=CC(NO)=CC=1.[F:22][C:23]([N:26]=[C:27]=[O:28])([F:25])[F:24]>O1CCCC1.[Pd]>[F:22][C:23]([F:25])([F:24])[NH:26][C:27]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:10])=[O:28]
Reactant: O=C=NC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pd]
Agent: NN
Agent: ONc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(NC(F)(F)F)N(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
p-Fluoronitrobenzene (14.1 grams; 0.1 mol) is dissolved in tetrahydrofuran (100 ml). Ten percent palladium on charcoal catalyst (0.1 gram) is added to the solution followed by hydrazine (6.0 ml; 0.1 mol), and the resulting mixture stirred at room temperature for about 48 hours with cooling as necessary. The reaction mixture, containing N-(4-fluorophenyl)hydroxylamine, is dried over anhydrous magnesium sulfate and filtered. To this solution is added trifluoromethyl isocyanate (11.1 grams; 0.1 mol) and the solution is stirred for about 15 minutes. The reaction mixture is concentrated by evaporation of solvent and the resulting precipitate is recovered by filtration to yield 1-trifluoromethyl-3-(4'-fluorophenyl)-3-hydroxyurea.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][CH2:14][CH2:13][O:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[Cl:16].O.C([O-])([O-])=O.[K+].[K+].B1(C=C)OB([CH:30]=[CH2:31])OB(C=C)O1.C1C=CN=CC=1>COCCOC.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>[Cl:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[CH:30]=[CH2:31])=[C:10]1[O:12][CH2:13][CH2:14][O:15][C:9]1=[CH:8][CH:7]=2
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Clc1cnc2ccc3c(c2c1Br)OCCO3
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: [K+]
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1c(Cl)cnc2ccc3c(c12)OCCO3
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of 10-Bromo-9-chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline (11.5 g, 38.4 mmol, 1 eq) in DME (425 mL, degassed with Argon), was added Pd(PPh3)4, the reaction was stirred under Argon for 20 mins. Water (122 mL), K2CO3 (5.32 g, 38.4 mmol, 1 eq) and the 2,4,6-trivinylcyclotriboroxane-pyridine complex (2.49 g, 15.4 mmol, 0.4 eq) were added, the mixture was then heated to reflux at 100° C. overnight. The reaction was then cooled, the product was extracted with water and DCM, dried over Na2SO4, filtered and evaporated to dryness. The solid obtained was the passed through silica with as a pale yellow solid (5.5 g, 58%). LC/MS (ES) m/z 247 (MH+ 100%); 1H-NMR (400 MHz, CDCl), 8.69 (1H, s, CHNHC), 7.59 (1H, d, J=9.2, CHCO), 7.18 (1H, dd, J=18, 12, CCH═C), 5.68 (1H, dd, J=12, 1, Hcis of CH2=C), 5.49 (1H, dd, J=18, 1, H trans of CH2=C), 4.37-4.339 (4H, m, 2×(CH2O)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.Cl[C:26](OC(Cl)(Cl)Cl)=[O:27].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH:46]=2)=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:26]([N:44]3[CH2:43][CH:42]=[C:41]([C:38]4[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=4)[CH2:46][CH2:45]3)=[O:27])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(C2=CCNCC2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(Cc2ccc(O)cc2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=CCN(C(=O)Oc3ccc(Cc4ccc(C)cn4)cc3)CC2)cc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a solution of 4-(5-methyl-pyridin-2-ylmethyl)phenol (0.8 mmol) prepared as described above and ethyldiisopropylamine (1.5 mmol) in CH2Cl2 (5 mL) at −30° C. was added trichloromethyl chloroformate (1.0 mmol). The solution was stirred at −30° C. for 10 min and at reflux temperature for 2 h. The solution was evaporated to dryness and redissolved in CH2Cl2 (5 mL) and cooled to 0° C. before addition of 4-(4-methoxyphenyl)-1,2,3,6-tetrahydro-pyridine (1.5 mmol). The solution was stirred at room temperature for 16 h evaporated to give the crude product which was purified by FC (Quad flash 40 CH2Cl2:Et2O:Heptane:Et3N 1:1:2:0.25->1:1:1:0.25) to give the title compound in 10% yield as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1.[Cl:24]N1C(=O)CCC1=O.O.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][C:7]=1[Cl:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(Cl)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (50 mg), N-chlorosuccinimide (23.9 mg) in DMF (1.5 ml) was stirred at 60° C. for 2 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of CHCl3 and MeOH. The fractions were concentrated in vacuo to obtain 6-(5-amino-6-chloro-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (30 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH:11]1(OS(C)(=O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CS(=O)(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCCCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-chloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclohexyl ester prepared in Example 132a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 239.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]([F:18])([F:17])[C:14](O)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:10]=[C:14]([C:13]([F:18])([F:17])[F:12])[N:8]2[CH3:9])=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1nc(Cl)nc(Cl)c1N
Product: Cn1c(C(F)(F)F)nc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-dichloro-N4-methylpyrimidine-4,5-diamine (400 mg) and trifluoroacetic acid (8 mL) was stirred for 8 hours while heating to reflux. Furthermore, the reaction mixture was stirred at 120° C. for 1.5 hours under microwave irradiation. After the reaction mixture was concentrated under reduced pressure, phenylphosphonic dichloride (1.8 mL) was added to the residue, and the mixture was stirred 180° C. for 2 hours. After the reaction mixture was cooled to room temperature, cold water (20 mL) was added thereto, then, the mixture was stirred, and the precipitate was collected by filtration. The obtained solid was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 90:10), whereby 2,6-dichloro-9-methyl-8-(trifluoromethyl)-9H-purine (435 mg) was obtained as a white solid.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.C(N(CC)CC)C.CC([Si](C)(C)[O:35][C@@H:36]([C@@H:45]([CH3:49])[C:46](=[O:48])[CH3:47])[C@@H:37]([CH3:44])[C:38](N(OC)C)=[O:39])(C)C.[NH2:52][C:53]([O:55][C@@H:56]([C@@H:91]([CH3:96])/[CH:92]=[CH:93]/[CH:94]=[CH2:95])[C@@H:57]([CH3:90])[C@H:58]([O:82][Si](C(C)(C)C)(C)C)[C@@H:59]([CH3:81])[CH2:60]/[C:61](/[CH3:80])=[CH:62]\[C@H:63]([CH3:79])[C@@H:64]([O:71][Si](C(C)(C)C)(C)C)[C@@H:65]([CH3:70])/[CH:66]=[CH:67]\[CH:68]=[O:69])=[O:54]>C(OCC)C>[CH3:49][C@@H:45]1[C@H:36]([OH:35])[C@@H:37]([CH3:44])[C:38](=[O:39])[O:48][C@H:46]1[CH2:47][C@H:68]([OH:69])/[CH:67]=[CH:66]\[C@@H:65]([C@H:64]([OH:71])[C@H:63](/[CH:62]=[C:61](\[CH2:60][C@@H:59]([C@@H:58]([OH:82])[C@@H:57]([C@@H:56]([O:55][C:53]([NH2:52])=[O:54])[C@H:91](/[CH:92]=[CH:93]\[CH:94]=[CH2:95])[CH3:96])[CH3:90])[CH3:81])/[CH3:80])[CH3:79])[CH3:70]
Reactant: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(C)=O
Reactant: C=C/C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O)[C@@H](C)/C=C\[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.18 g (6.79 mmol, 10 equiv.) of (+)-β-chlorodiisopinocamphenylborane in 4 mL of diethyl ether at 0° C. is added 1.04 mL (11 equiv., distilled over calcium hydride) of triethylamine and then a solution of 2.25 g (6.79 mmol, 10 equiv.) of the compound of Example 1 in 3 mL of diethylether. After stirring for 2 hours at 0° C., the mixture is cooled to −78° C., after which time a pre-cooled (−78° C.) solution of 450 mg (0.679 mmol) of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15E)-13-[(amino-carbonyl)oxyl]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenal in 4 mL of diethylether is added via cannula. After the resultant mixture is maintained at a temperature of −78° C. for 3 hours, it is transferred to a freezer (−27° C.) for 16 hours. The reaction is then quenched with 8 mL of methanol (the pH of which is adjusted to 7 with 12 mL of buffer solution) and 4 mL of 50% hydrogen peroxide solution at 0° C. After stirring for 2 hours at 25° C., the organic layers are separated. The aqueous layer is then extracted five times with 25 mL portions of dichloromethane. The combined organic layers are then dried over magnesium sulfate, concentrated using a rotary evaporator and chromatographed (Biotage, silica gel, gradient 10-30% ethyl acetate/hexane) to yield the desired compound as a colorless, highly viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[N:18]([O-])=[O:19].[Na+]>C(O)C.O>[N:18]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8]1)=[O:19]
Reactant: c1ccc2c(c1)CC(c1ccncc1)CN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=NN1CC(c2ccncc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 3-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline (0.4 g, 0.0019 mol) in ethanol (1.7 mL) was added 1N hydrochloric acid (1.7 mL). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (0.262 g, 0.0038 mol) in water (5.5 mL) was added at 0° C. The reaction mixture was warmed to RT and stirred for 1 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure to obtain product as a brown colored oil (0.41 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1Cl.[NH2:10][NH2:11].C([O-])([O-])=O.[Na+].[Na+]>C1(O)CCCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[NH:10][NH2:11]
Reactant: NN
Reactant: Fc1cncc(Br)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OC1CCCCC1
Product: NNc1c(F)cncc1Br

Procedure:
3-bromo-4-chloro-5-fluoro-pyridine (500 mg, 2.376 mmol), hydrazine (761.4 mg, 745.7 μL, 23.76 mmol), Na2CO3 (503.7 mg, 4.752 mmol) in cyclohexanol was heated at 100 C overnight. The reaction mixture was filtered on celite and loaded on a SCX column, washed with DCM/MeOH mixtures and was eluted with a 2M solution of NH3 in MeOH. The filtrate was concentrated in vacuo and the 3/1 mixture of 3-bromo-5-fluoro-4-hydrazinylpyridine and 3-bromo-4-chloro-5-hydrazinylpyridine was used in next step without further purification. MS (ES+) 205.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(=O)(O)[O-].[K+].Cl[CH2:17][C:18](Cl)=[O:19].[NH2:21][C@H:22]([CH3:25])[CH2:23][OH:24]>O.CCOC(C)=O>[OH:24][CH2:23][C@H:22]([NH:21][CH2:17][C:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:19])[CH3:25]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](N)CO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CO)NCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
3-Nitroaniline (5.0 g, 36.2 mmol) was combined with EtOAc (50 mL) and 20% aq potassium bicarbonate (25 mL). The biphasic mixture was cooled to 0° C. (ice water bath) and treated with chloroacetyl chloride (2.9 mL, 36.2 mmol) dropwise over 30 min. The reaction mixture was warmed up to room temperature and stirred for 30 min. The reaction mixture was followed up by HPLC. The aqueous layer was removed. The organic layer was combined with (2R)-2-amino-1-propanol (8.5 mL, 108.6 mmol), heated to 60° C. for 3 h. HPLC analysis showed no SM was left. Water was added to reaction mixture and reheated to 60° C. The aqueous layer was removed and organic layer was washed by brine (60 mL×3). Evaporated solvent to dryness on vacuum and the yellow solid was stirred with 100 mL of 30% EtOAc in hexane. The solid was collected and washed with solvent (30% EtOAc in Hexane) 70 mL×3. The off white solid was collected and examined by HPLC and 1H NMR. The solid was dried on high vacuum over night which produced a off white solid N2-[(1R)-2-hydroxy-1-methylethyl]-N1-(3-nitrophenyl)glycinamide (5.65 g, 62% yield). MS: M(C11H15N3O4)=253.26 (M+H)+=254.
Reaction SMILES: ClC1C=CC(O)=C(C2C(C#CC3C=CC(NC([C@H]4CCCCN4)=O)=CC=3)=CN(CCO)N=2)C=1.C(OC([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47](=[O:73])[NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[C:56][C:57]2[C:58]([C:65]3[CH:70]=[C:69]([Cl:71])[CH:68]=[CH:67][C:66]=3[OH:72])=[N:59][N:60]([CH2:62][CH2:63][OH:64])[CH:61]=2)=[CH:51][CH:50]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:71][C:69]1[CH:68]=[CH:67][C:66]([OH:72])=[C:65]([C:58]2[C:57]([C:56]#[C:55][C:52]3[CH:53]=[CH:54][C:49]([NH:48][C:47]([CH:42]4[CH2:43][O:44][CH2:45][CH2:46][NH:41]4)=[O:73])=[CH:50][CH:51]=3)=[CH:61][N:60]([CH2:62][CH2:63][OH:64])[N:59]=2)[CH:70]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Agent: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)C1COCCN1
Yield: 74 %

Procedure:
Using the same procedure for the preparation of 5A, treatment of compound 16A (870 mg) with TFA (10 mL) in methylene chloride (10 mL) gives compound 17A in 74.0% yield. 1H NMR (DMSO-d6, 500 MHz) δ 10.67 (s, 1H), 10.02 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 7.73 (d, 2H, J=8.0 Hz), 7.47 (d, 2H, J=8.5 Hz), 7.30 (d, 1H, J=9.0 Hz), 6.99 (d, 1H, J=8.5 Hz), 5.01 (br s, 1H), 4.26 (br s, 2H), 3.83 (d, 1H, J=7.5 Hz), 3.78 (d, 2H, J=2.5 Hz), 3.61 (m, 3H), 3.52 (m, 2H), 3.43 (t, 1H, J=10.0 Hz), 2.85 (d, 1H, J=13.0 Hz), 2.75 (t, 1H, J=11.0 Hz). LCMS (ESI) m/z 467.09 (MH+, 100); HPLC: tR=3.92 min.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[OH:11][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h
Yield: 28203.2 %

Procedure:
To a stirred solution of L-Leu-OH (5.0 g, 38.2 mmol) in 1N H2SO4 (50 mL) at 0° C. was slowly added over 1 1/2 h a solution of sodium nitrite (NaNO2 ) (7.5 g, 0.11 mmol) in water (20 mL) while maintaining the temperature at 0° C. The reaction mixture was gradually warmed to R.T., stirred for 24 h, and concentrated to give a white solid. The solid was extracted with ether (5×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give (2S)-2-hydroxy-4-methylpentanoic acid as an oil (4.1 g, 81.2%): 1H NMR (CDCl3, 300 MHz) δ 0.98 (d, 6 H, J=12.0 Hz), 1.57-1.67 (m, 2 H), 1.82-1.93 (m, 1 H), 4.36 (t, 1 H, J=6.0 Hz) ppm.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=[CH:5][N:6]([CH3:8])C.[NH2:24][C:25]1[NH:29][N:28]=[CH:27][C:26]=1C#N>C(O)(=O)C.C(OCC)(=O)C.CCCCCC>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3](=[O:23])[N:29]3[N:28]=[CH:27][C:26]([C:25]#[N:24])=[C:8]3[NH:6][CH:5]=2)=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(=CN(C)C)c1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1cn[nH]c1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cnn2c(=O)c(-c3ccc(OCc4ccccc4)cc3)c[nH]c12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of 1.21 g (3.9 mmol) of 2-(4-benzyloxy-phenyl)-3-dimethylamino-acrylic acid methyl ester and 0.422 g (3.9 mmol) of 5-amino-1H-pyrazole-4-carbonitrile in 5 mL of acetic acid (HOAc) was heated at reflux overnight, during which time a precipitate formed. The reaction mixture was cooled to rt, diluted with 20% ethyl acetate in hexane solution, and filtered to give 0.86 g (65% over 2 steps) of 6-(4-benzyloxy-phenyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a tan colored solid as indicated by 1H NMR; LC-MS—calcd for C20H14N4O2 [M++H]+: 343.11, found: 343.1.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].C1(=O)OC(=O)[C@H]2CC=CC[C@@H]12.[S:20]([O-:24])([O-:23])(=[O:22])=[O:21].[OH-:25].[Na+:26].C(O)(=O)C=C>O>[S:20]([O:24][O:25][S:20]([O-:23])(=[O:22])=[O:21])([O-:23])(=[O:22])=[O:21].[Na+:26].[Na+:26].[OH:25][OH:5]
Reactant: [OH-]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=CC(=O)O
Agent: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])OOS(=O)(=O)[O-]
Product: OO
Temperature: 95 °C
Reaction time: 0.03 h

Procedure:
To a two liter, 4-neck flask equipped with a mechanical stirrer, reflux condenser, thermometer, and inlets for the gradual addition of monomer and initiator solution was added 90.0 grams of deionized water, 62.5 grams of maleic acid, 67.07 grams of cis-1,2,3,6-tetrahydrophthalic anhydride, 5.0 grams of a 0.15% aqueous ferrous sulfate heptahydrate solution, 1.3 grams of a 0.15% aqueous coppper sulfate solution and 117.5 grams of 50% by weight aqueous sodium hydroxide. The contents of the flask were heated to 95° C. A monomer feed of 112.5 grams of acrylic acid, and an initiator solution of 7.5 grams of sodium persulfate, 41.6 grams of 30% by weight aqueous hydrogen peroxide and 50.0 grams of deionized water were prepared. 12.5 grams of the monomer feed were added to the flask. After two minutes, 10.0 grams of the initiator solution was added to the flask. The contents of the flask were then heated to 100° C. The remainder of the monomer feed and initiator solution were then fed into the flask linearly and separately while stirring over two hours and fifteen minutes. Once the additions were complete, the system was kept at 100° C. for 30 minutes. The system was then cooled to 60° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[Cl:16])=[C:4]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[N:3]=1.[Cl:24]C1C=C(Cl)C=CC=1CC#N>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[N:3]=1
Reactant: CCOC(OCC)c1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: N#CCc1ccc(Cl)cc1Cl
Product: CCOC(OCC)c1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared in a manner analogous to 2,4-diamino,5-(2,3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine (Example 18.1) from 2,4-dichlorophenylacetonitrile, mp. 225° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[NH:36][C:37]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([CH3:23])[C:19](=[O:24])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:38]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1nc2c(Oc3ccc(N)c4ccccc34)ccnc2[nH]c1=O
Product: Cc1nc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)ccnc2[nH]c1=O

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly pink solid (50 mg, 61%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([CH2:7][O:8][N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2)([OH:6])=[O:5].O>C(OCC)C.CN(C)C=O>[CH3:3][O:5][C:4]([CH2:7][O:8][N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2)=[O:6]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CON=c1c2nccc3cccc(c32)n2cccc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)CON=c1c2nccc3cccc(c32)n2cccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 0.57M solution of diazomethane in diethyl ether (108 cc.) is added to a suspension of 7-carboxymethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (15 g.) in dimethylformamide (150 cc.) cooled to 0° C. The mixture is kept at between 0° and 5° C. for 3 hours and is then allowed to return to a temperature of about 20° C. Water (450 cc.) is then added, the mixture is cooled in an ice-water bath and the yellow crystals thus obtained are filtered off. After drying, the crude methyl ester (14.17 g.) is obtained. After recrystallisation from ethyl acetate (280 cc.), the 7-methoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline obtained melts at 148 ° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:13][C:14]([CH3:18])=[CH:15][CH:16]=O.C1(B(O)O)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[O:11][C:14]([CH3:18])([CH3:13])[CH:15]=[CH:16]2
Reactant: CC(C)=CC=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2c(c1)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
25 g methyl-4-hydroxyphenylacetate, 14.5 ml 3-methylbut-2-enal and 18.3 g phenylboronic acid were placed together under nitrogen atmosphere in 1 l dry toluene and heated to boiling for 7 hours under reflux cooling. Then 60 ml glacial acetic acid was added to this receiving solution at room temperature (=RT) and the mixture was again heated to boiling for 7 hours under reflux cooling. It was allowed to cool to room temperature, the solvent was largely evaporated at reduced pressure and the remaining residue was poured into 300 ml of a 1:1 (v/v) mixture of ethyl acetate (═EA) and water. The pH value was adjusted to 5 by addition of solid sodium bicarbonate, the organic phase was separated off and largely evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: petroleum ether/EA 10:1 v/v) yielded 16 g methyl-(2,2-dimethyl-2H-chromen-6-yl)acetate as pale yellow oil.