Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([C:25]#[N:26])=[N:15][C:14]=2[N:13]([CH3:27])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([CH2:25][NH2:26])=[N:15][C:14]=2[N:13]([CH3:27])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOCn1c(C#N)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOCn1c(CN)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Yield: 105.4 %

Procedure:
A suspension of (R)-1-(5-acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (750 mg, 1.92 mmol) and 10% palladium on carbon (250 mg) in glacial acetic acid (40 ml) was treated with hydrogen gas (80 psi) on a Parr shaker for 3 hours. The mixture was filter through a pad of celite and then the filtrate was concentrated under reduced pressure to provide the acetic acid salt of (R)-1-(5-Acetoxyhexyl)-8-aminomethyl-7-ethoxymethyl-3-methylxanthine (800 mg, 91% yield) as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](N)=[N:9][NH:10][C:3]=12.N([O-])=O.[Na+]>O.CC(O)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12
Reactant: Nc1n[nH]c2c(I)ccnc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccnc2cn[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a suspension of 7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (23 g) in water (90 mL) and AcOH (75 mL) was added dropwise a solution of sodium nitrite (12.6 g) in water (90 mL) over 30 minutes at 0° C. The mixture was warmed to room temperature and stirred for 24 hours. Then the mixture was cooled to 0° C. again and stirred for another 0.5 hour to give a solid which was collected by filtration and washed with cold water. The solid was suspended in aqueous HI (20 mL 50% HI diluted to 300 mL with water) and dimethoxymethane (600 mL). This mixture was heated to 80° C. for 3 hours, then cooled to room temperature, neutralized with Na2CO3 solution, and then extracted with ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give a residue. This residue was purified by column chromatography eluting with 1:2 petroleum ether:ethyl acetate to afford the title compound as a light yellow solid (7.8 g). 1H-NMR (400 MHz, DMSO-d6) 7.86 (d, J=4.4 Hz, 1H) 8.16 (d, J=4.4 Hz, 1H) 8.46 (s, 1H) 13.67 (s, 1H).
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([F:37])[C:14]1[CH:36]=[CH:35][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH:20]C(OCC2C=CC=CC=2)=O)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:9]([O:8][P:6]([CH:13]([F:37])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:31]([O:33][CH3:34])=[O:32])[NH2:20])=[CH:35][CH:36]=1)([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Compound 20 (1.09 g, 2.03 mmol) in anhydrous MeOH (50 mL) is hydrogenated over 10% Pd.C (436 mg) under H2 (45 psi) in a Parr apparatus. The vessel is evacuated and replenished with H2 at approximately 30 minute intervals. After 4 hours, the mixture is removed, filtered through celite and solvent removed under reduced pressure, yielding crude 21 (813 mg). Purification by silica gel chromatography affords pure 21 (694 mg, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COC(OC)C.O.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>[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: [Ba+2]
Solvent: O
Product: Cc1cc(C)c(-c2cccc([N+](=O)[O-])c2C)c(C)c1
Yield: 93.7 %

Procedure:
A solution of 2-bromo-6-nitrotoluene (10.0 g, 46 mmol), mesitylboric acid (8.3 g, 51 mmol), Pd(PPh3)4 (2.7 g, 2.31 mmol) and barium hydroxide octahydrate (21.9 g, 69 mmol) in 2,2-dimethoxyethane (300 mL) and water (50 mL) was heated under reflux for six hours. The mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (0-1% ethyl acetate/hexane), to give the title compound (11.0 g) as white crystals.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].C([O-])([O-])=O.[K+].[K+]>O>[NH:6]1[C:10]2[C:3](=[CH:2][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmmol) K2CO3 and 3 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95° C. and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 5 h hour the conversion was approximately 37%. After 22 h full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25° C. and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was 95.6%, ee>99%.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]([C:55]1[CH:62]=[CH:61][C:58]([C:59]#[N:60])=[CH:57][CH:56]=1)[CH2:28][O:29][CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)(C(C)(C)C)(C)C>O1CCCC1.O>[OH:26][CH:27]([C:55]1[CH:56]=[CH:57][C:58]([C:59]#[N:60])=[CH:61][CH:62]=1)[CH2:28][O:29][CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 mmol of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) are added to a solution of 1 mmol of 4-[1-(tert-butyldimethylsilanyloxy)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in 5 ml of tetrahydrofuran, and the solution is stirred at room temperature for 1 hour. The reaction solution is then diluted with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[C:14]1([CH2:13][N:20]2[C:5]([NH2:6])=[C:4]([C:3]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])[N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(-c2nnn(Cc3ccccc3)c2N)c(C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.8 %

Procedure:
A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl3, 300 MHz):7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M+H).
Reaction SMILES: [Li+].[BH4-].[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=[C:5]12>C1COCC1.C(Cl)Cl.O=[Mn]=O>[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[C:14]([CH:16]=[O:17])[N:15]=[C:5]12
Reactant: CCOC(=O)c1cn2c3ccccc3n(C)c2n1
Agent: O=[Mn]=O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c2ccccc2n2cc(C=O)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To stirred solution of LiBH4 (1.79 g, 82 mmol) in THF at 0° C., ethyl 9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carboxylate (2.5 g, 10.3 mmol) was added drop wise. The reaction mixture was refluxed for 2 hrs and cooled to room temperature. Ti was carefully quenched with ice cold water and acidified with Con. HCl to pH 4. The reaction mixture was stirred at room temperature for 1 hr and basified with K2CO3. The residue was extracted with chloroform:methanol (3:1) and dried over anhydrous MgSO4. It was filtered and concentrated. Yield. 1.3 g (65%). (M+H) 202. The residue (1.3 g, 6.4 mmol) was oxidised with MnO2 (5.0 g) in CH2Cl2 under refluxing condition. After the completion, reaction mixture was filtered and concentrated. It was purified by SiO2 column chromatography by eluting it with 1:1 ethyl acetate:hexane. Brown solid. Yield. 330 mg (25%); (M+H) 200.
Reaction SMILES: [Br:1]Br.[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[Br:1][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[F:18])[CH:13]=[O:14])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: BrBr
Solvent: ClCCl
Product: O=Cc1ccc(F)c(Oc2ccc(Br)cc2)c1
Reaction time: 1 h

Procedure:
A solution of bromine (9.60 g, 0.06 mmole) in methylene chloride (10 ml) was added dropwise to a solution of 3-phenoxy-4-fluorobenzaldehyde (10.8 g, 0.05 mmole) in methylene chloride (40 ml) at 20° C. taking a period of 1 hour with stirring. After the addition was finished, the reaction was continued for further 3 hours at the same temperature. The resulting solution was washed with water and then dilute aqueous potassium sulfite solution to remove the remaining bromine in the organic layer. The organic layer obtained was washed with a dilute aqueous sodium carbonate solution and then a dilute aqueous sodium chloride solution, and dried over anhydrous sodium sulfate and concentrated.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]CC)=[O:17])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)O)cn2)CC1
Reaction time: 1 h

Procedure:
35.6 g of crude ethyl trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate are treated with 62 ml of ethanol and a solution of 46.6 g of sodium hydroxide in 312 ml of water and heated to boiling for 1 hour. After cooling, the mixture is acidified with 220 ml of half-concentrated hydrochloric acid, left to stand for 1 hour in an ice-bath and then suction filtered. The material on the suction filter is washed with water and dried in vacuo at 50° C. over potassium hydroxide. For purification, the crude product is recrystallized from dioxan/water. There is obtained trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylic acid; m.p. 184°-185.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1)[NH2:24].N1C=CC=CC=1>CC#N>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[N:22]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:20])[F:18]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 5 (4.32 g, 15.4 mmol) in MeCN (15 mL) was added 1-ethyl-3-dimethyl aminopropylcarbodiimide (4.14 g, 21.6 mmol) followed by Intermediate 72 (2.81 g, 17.0 mmol). The mixture was stirred at RT for 18 hours and then pyridine (5 mL) added. The mixture was heated under microwave irradiation at 150° C. for 30 minutes. The solvent was removed in vacuo and the residue partitioned between DCM and H2O. The layers were separated, the organic layer washed with H2O and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was recrystallised from EtOAc and petrol to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.63 (1H, s), 8.40 (1H, d, J=8.0 Hz), 8.20 (2H, d, J=8.0 Hz), 7.54 (2H, d, J=7.9 Hz), 7.47 (1H, d, J=7.9 Hz), 7.38-7.21 (3H, m), 7.16 (1H, d, J=7.5 Hz), 4.81 (2H, d, J=5.7 Hz), 2.14-1.94 (3H, m). LC/MS (Method A): 411 (M+H)+. HPLC (Method G) Rt 4.50 min (Purity: 97.9%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[N+:14]([O-])([OH:16])=[O:15]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)ccc1F
Reaction time: 0.5 h

Procedure:
To a cooled solution (0°-5° C./-15° C. with CO2 /acetone/water) of conc. sulfuric acid (600 ml) and 90% nitric acid (330 ml) in a three-necked flask equipped with a mechanical stirrer and thermometer was added 1,4-difluorobenzene dropwise (300 g., 2.63 moles) over 2.5 hours. After an additional 30 min. stirring, the mixture was carefully poured into ice and extracted with ethyl ether (3×600 ml). The organic layers were washed with brine, water, 5% sodium bicarbonate solution, dried over (Na2SO4) and evaporated in vacuo. The orange liquid was distilled under vacuum to obtain 1,4-difluoro-2-nitrobenzene, b.p. 102°-105° C. at 30 torr.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Cc1cccnc1O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1cccn(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)c1=O
Temperature: 130 °C
Yield: 15.7 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (66 mg, 0.15 mmol), 2-hydroxy-3-methylpyridine (45 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (10 mg). MS 425.0 and 427.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[CH:4]=O.[NH2:11][NH2:12]>C(O)C>[Cl:1][C:2]1[C:3]2[CH:4]=[N:11][NH:12][C:6]=2[CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: NN
Solvent: CCO
Product: Clc1nccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 19 %

Procedure:
To a mixture of 2-chloro-4-iodonicotinaldehyde (1.0 g, 3.7 mmol) in ethanol (6.0 mL) was added 3.0 mL of hydrazine (excess). The mixture was stirred at room temperature for 15 h and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with dichloromethane (300 mL). The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and stirred for 5 min. The precipitated solid was isolated by filtration and dried to give the desired intermediate 4-chloro-1H-pyrazolo[4,3-c]pyridine as a grey solid (110 mg, 19% yield), which was used in the next step without further purification. LCMS(ESI) m/z: 154.1 [M+H+]
Reaction SMILES: [C:1](OC)(=[O:5])[C:2]([CH3:4])=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=1[NH2:17]>C(O)C>[CH3:8][O:9][C:10]1[C:11]2[N:17]=[C:2]([CH3:4])[C:1](=[O:5])[NH:16][C:12]=2[N:13]=[CH:14][CH:15]=1
Reactant: COc1ccnc(N)c1N
Reactant: COC(=O)C(C)=O
Solvent: CCO
Product: COc1ccnc2[nH]c(=O)c(C)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-pyridin-2-ylamine (5 g) in 96% aq H2SO4 (20 mL) at 0° C. was added a mixture solution of 70% aq HNO3 (2.5 mL) and 96% aq H2SO4 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2 h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3 mL) and NaOMe (125 mg) was added before the mixture was stirred at 60° C. for 16 h. 37% aq HCl was added drop-wise to adjust pH to 6. The mixture was cooled to 0° C., and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10% palladium on charcoal at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3 h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5:1 to 0:1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-1-yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (10 mL) and DCM (60 mL). Hydrazine monohydrate (3.6 g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)-hydrazine IIe (0.9 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[C:16]([OH:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH2:13]>>[CH3:10][C:11]1[CH:17]=[C:16]([OH:18])[C:15]([CH3:19])=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=[CH:17][C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc(O)c(C)cc1N
Product: Cc1cc(Nc2ncc(F)c(Nc3cc(C)c(O)cc3C)n2)c(C)cc1O

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2,5-dimethyl-4-hydroxyaniline were reacted to yield N2,N4-bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.63 (d, 1H, J=4.2 Hz), 7.05 (s, 1H), 6.97 (s, 1H), 6.64 (1H), 6.54 (s, 1H), 2.12 (s, 6H), 2.06 (s, 3H), 2.03 (s, 3H), 2.03 (s, 3H); 19F NMR (CD3OD): −48488; LCMS: ret. time: 18.28; purity; 94%; MS (m/e): 369 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:44])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([NH:42][CH3:43])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:44])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[CH:41]=[C:40]([NH:42][CH3:43])[N:39]=[CH:38][N:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CNc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-[3-(6-methylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K54) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (166 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)=S)=[CH:4][CH:3]=1.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: C[C@H]1CN(C(=S)c2ccccc2F)c2cc(Br)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(c2noc3ccccc23)c2cc(Br)ccc2N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charged with a solution of (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanethione (0.021 g, 0.057 mmol) in dimethylsulfoxide (0.5 mL) and hydroxylamine (50% in water, 0.035 mL, 0.575 mmol). The vial was capped, and the solution heated to 100° C. for 90 min. Heating was increased to 150° C. for 3 h, and then the solution was stirred at rt overnight. Additional hydroxylamine (50% in water, 0.035 mL, 0.575 mmol) was added and heating resumed at 150° C. for 5 h. Potassium carbonate (ca. 10-15 mg) was added and heating resumed at 100° C. for 5 h. The mixture was diluted with water (1 mL) and extracted with dichloromethane. The dichloromethane extract was washed with 5% aqueous sodium chloride solution (1 mL) and concentrated. The crude product was purified by preparative thin layer chromatography (1×1000 micron plate, eluting with 4:1 hexanes-ethyl acetate). The major band was isolated to afford (S)-3-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]isoxazole (0.010 g, 51%). MS (ESI, pos. ion) m/z 344, 346 [M+1].