Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]>CCCCCC>[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(F)c([N+](=O)[O-])c1)C(=O)OCC
Reaction time: 2 h
Yield: 89.3 %

Procedure:
50 g of 4-fluoro-3-nitroaniline and 69 g of ethoxymethylene malonic acid-diethyl ester were heated for 3 hours to 120° C. The mixture was added to n-hexane, stirred for 2 hours, and the crystalline material was suctioned off and dried in a vacuum at room temperature. 93 g of N-(4-fluoro-3-nitrophenyl)-aminomethylene malonic acid diethyl ester is obtained. The latter is added in 3 portions of 31 g to respectively 150 ml of a mixture that consists of 26.5% diphenyl and 73.5% diphenyl ether (DOWTHERM A⊕) that is preheated to 260° C., and it is stirred for 30 minutes at this temperature. After cooling, it is diluted with 500 ml of n-hexane, and the precipitate is suctioned off. A total of 64 g of a mixture of 1,4-dihydro-6-fluoro-5-nitro-4-oxo-quinoline-3-carboxylic acid ethyl ester and 1,4-dihydro-6-fluoro-7-nitro-4-oxo-quinoline-3-carboxylic acid-ethyl ester is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:11][C:7]=1[CH:6]=[CH:5]2.C1C(=O)N([I:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[N:11][C:7]=1[CH:6]=[C:5]2[I:34]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(I)c3cc(Br)ccc3c2[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
(S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.990 g, 2.38 mmol) was suspended in DMF (8 mL) and treated with NIS (1.03 g, 4.59 mmol). The reaction mixture was stirred at 70° C. for 2 d, then cooled to RT. The mixture was then diluted with EtOAc and the organic solution was washed with 3× with brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30% to 55% EtOAc/Hex) to afford (S)-tert-butyl 2-(7-bromo-5-iodo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (753 mg, 58%).
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[NH2:8].CCN(CC)CC.[H][H]>CO.[Pd]>[F:10][C:5]1[C:6]([F:9])=[C:7]([NH2:8])[CH:2]=[C:3]([F:11])[N:4]=1
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1cc(F)nc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of 3-chloro-2,5,6-trifluoro-pyridin-4-ylamine (1.82 g, 10 mmol), 5% Pd/C (0.5 g), and Et3N (3.04 g, 30 mmol) in 50 mL of MeOH was equipped with a balloon of hydrogen gas and stirred at room temperature overnight. The solution was filtered through diatomaceous earth (Celite®). The filtrate was concentrated under vacuum and the residue was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 1.33 g (90%) of the desired product. MS (DCI) m/e 149 (M+H)+.
Reaction SMILES: C([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][C:30]2C=CC=CC=2)=[C:6]2[CH:36]=[CH:37][CH:38]=[CH:39][C:5]=12)C>[Pd].C(O)C>[CH2:29]([O:28][C:7]1[C:8]2[C:9](=[O:27])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:11](=[O:13])[C:12]=2[C:4]([OH:3])=[C:5]2[CH:39]=[CH:38][CH:37]=[CH:36][C:6]=12)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.5 %

Procedure:
10% Palladium on carbon (0.175 g) was suspended in ethanol (150 ml), to this was added ethyl (4-{4-(ethyloxy)-1,3-dioxo-9-[(phenylmethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}-3-fluorophenyl)acetate (1.75 g, 3.32 mmol). The reaction was stirred at room temperature under an atmosphere of hydrogen for 3 hours. This was filtered through a bed of celite under a blanket of argon, and washed with dichloromethane. The filtrate was evaporated to give a yellow solid (1.56 g, 3.57 mmol). LC/MS: Rt=3.50, [MH]+ 438.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[N:13][N:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([O:40][CH:41]([CH3:43])[CH3:42])[C:26]([F:39])=[C:27]([CH:38]=1)/[CH:28]=[N:29]/[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH3:21]>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([N:29]([CH2:28][C:27]2[CH:38]=[C:23]([O:22][CH2:20][CH3:21])[CH:24]=[C:25]([O:40][CH:41]([CH3:43])[CH3:42])[C:26]=2[F:39])[C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[N:13][N:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: c1ccc(COCn2cnnn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nnnn2COCc2ccccc2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 24.3 %

Procedure:
To a solution of Intermediate 12.1 (50.0 mg, 0.263 mmol) in 2 mL THF at −78° C. was added 1.6 M solution of BuLi in THF (181 μL, 0.289 mmol). The mixture was stirred at −78° C. for 2 min, then a solution of Intermediate 7.3 (86 mg, 0.263 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at −78° C. for 30 min, was allowed to warm to rt over 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (25 to 30% EtOAc/hexanes, stepwise gradient) to afford 33 mg of Intermediate 12.2 as yellow residue.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:6](O)=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:9][C:10]=1[CH3:11].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:6]1[C:5]([O:4][C:3]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:2]=2[Cl:1])=[C:10]([CH3:11])[N:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2O)c1
Product: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2Cl)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.72 g of 5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-ol were mixed with 3.3 ml of POCl3. The reaction mixture was stirred at 120° C. for 2 hours, thereafter the excess reagent was distilled off. The residue was taken up in chloroform and washed with water, 1N NaOH and water. The organic phase was dried, concentrated and the residue was recrystallized from ether. There were obtained 1.48 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidin-2-yl]-morpholine, m.p. 134° C., MS: M=369.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1.C(Cl)(=O)C(Cl)=O.C[N:30](C=O)C.N.O1CCOCC1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH2:30])=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid, intermediate 9 (133 mg, 1 equiv) and oxalyl chloride (60 μL, 1.5 equiv) in chloroform (2.2 ml), was added DMF (3 μL, 0.1 equiv). The mixture was allowed to stir at room temperature and until the bubbling ceased. Then, to this mixture, was added a solution of 0.5 M ammonia in dioxane (2.7 ml, 3.0 equiv). The mixture was stirred at room temperature for 1 h. It was concentrated under vacuum. The resulting residue was suspended in ethyl acetate (200 ml) and washed with saturated solution of sodium bicarbonate (50 ml×2). The organic layer was washed with brine (10 ml), dried, filtered and evaporated to give 120 mg of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carboxamide (91%) as an orange solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: C[C@@H](O)[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product (12.0 g) containing N,N-dimethyl-L-threoninamide hydrochloride obtained in B) and triethylamine (20.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (8.8 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (3.0 g).
Reaction SMILES: Br.[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.[N+:13]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([NH2:25])=[C:18]([NH2:26])[CH:17]=1)([O-:15])=[O:14]>CS(C)=O>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[CH:2]=[N:26][C:18]3[C:19](=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=3)[N:25]=2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2ncc(-c3ccc(Cl)c(Cl)c3)nc2cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 24 h

Procedure:
48% aqueous HBr (8.8 M) (3.4 ml, 30 mmol) was slowly added to a stirred solution of 3,4-dichloroacetophenone (1.89 g, 10 mmol) in DMSO (17 ml). The solution was stirred in an open flask at 55° C. for 24 hours. The solution was poured onto ice, the solid product was filtered, washed with water, and redissolved in ethanol (18 ml). 4,5-Dinitro-1,2-phenylene-diamine (890 mg, 4.5 mmol) was added and the mixture was heated to reflux for 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 71592 %

Procedure:
In a 3 L 3 neck flask with a mechanical stirrer, DMAP (11.5 g, 0.10 mmol) was added to a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (105 g, 0.95 mmol) and in pyridine (750 mL). A solution of (BOC)2O (222 g, 1.02 mol) in pyridine (750 mL) was slowly added to the previous solution while the temperature was kept between 20 and 25° C. The mixture was stirred under nitrogen for 20 h. The reaction mixture was evaporated to dryness then triturated in 500 mL of MeOH at rt for 3 h then 30 min at 0° C. The suspension was filtered on a buchner funnel and washed with cold ethanol. The white solid was dried to afford 175 g (70%) of 3-tert-Butoxycarbonylamino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([OH:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCOCC1>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][O:22][CH2:1][CH2:2][OH:3]
Reactant: C1CO1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCOCCO

Procedure:
In 50 ml of dioxane, 20.00 g of polyethylene glycol monooleyl ether (average molecular weight 4,268) obtained by addition of ethylene oxide to an oleyl alcohol in the presence of an alkali catalyst and 1.90 g of triethyl amine were dissolved. The resultant solution and a solution of 1.85 g of p-toluenesulfonyl chloride in 10 ml of dioxane slowly added dropwise thereto were left reacting at 60° C. for two hours. The reaction product was refined by being dissolved with 200 ml of acetone added thereto, then cooled to 0° C., and left standing to allow sedimentation of the product aimed at. Then, a solution of 6.50 g of the product mentioned above in 30 ml of DMF and 0.55 g of potassium phthalimide added thereto were left reacting at 90° C. for two hours. The reaction product was refined by being dissolved with 60 ml of acetone added thereto, then cooled to 0° C., and left standing to allow sedimentation of the product aimed at. Subsequently, a solution of 6.00 g of the product mentioned above in 30 ml of ethanol and 1.00 g of hydrazinc hydrate added thereto were left reacting as refluxed for two hours. The reaction product was refined by being dissolved with 60 ml of acetone added thereto, then cooled to 0° C., and left standing to allow sedimentation of the product aimed at. Consequently, 5.20 g of an oleyl alcohol macromer possessed of amino groups at the terminals thereof was obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH2:4].[C:5]([C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)(=O)[CH3:6].C([BH3-])#N.[Na+]>CO.CC(O)=O>[F:1][CH2:2][CH2:3][NH:4][CH:5]([C:8]1[C:9]([C:29]([F:31])([F:32])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)[CH3:6]
Reactant: NCCF
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCCF)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 100 °C
Yield: 5 %

Procedure:
To a solution of 2-fluoroethanamine (107 mg, 1.689 mmol) in MeOH (1.5 mL), AcOH was added until the pH reached 5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) was added before the addition of sodium cyanoborohydride (7.58 mg, 0.121 mmol). The reaction was heated by microwave irradiation to 100° C. for 20 min. The reaction mixture was filtered before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 4 before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (2.9 mg, 0.006 mmol, 5%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40]([CH2:42][CH2:43][OH:44])[CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][N:40]([CH2:42][CH2:43][OH:44])[CH:41]=1
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cnn(CCO)c3)n(-c3ccccc3)c(=O)c12
Yield: 8.8 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.12 mmol) was treated with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (66 mg, 0.28 mmol, prepared according to Perry, Benjamin Garfield; Sabin, Verity Margaret from PCT Int. Appl. (2009), WO 2009122148 A1 20091008), sodium carbonate (2M, 565 μl, 1.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.02 mmol) according to the method described in Example 3 to give 5 mg (8% yield) of the title compound. Purity 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+]>O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2ncccc2C(=O)O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CCc2ncccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84.1 %

Procedure:
10% Pd/C (2.21 g, 2.08 mmole) was added to a solution of 2-[2-(4-methoxyphenyl)ethenyl]nicotinic acid (5.31 g, 20.80 mmole) and 1.0 N NaOH (23 mL, 23 mmole) in H2O (81 mL), and the mixture was shaken at RT under H2 (50 psi) on a Parr apparatus. After 4.5 hr, the mixture was filtered through celite®, and the filtrate was acidified to pH 5 with glacial acetic acid. The solid was collected by suction filtration, washed with H2O, and dried in high vacuum at 45° C. to afford the title compound (4.50 g, 84%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.65 (dd. J=4.7, 1.7 Hz, 1H), 8.15 (dd, J=7.8, 1.7 Hz, 1H), 7.35 (dd, J=7.8, 4.7 Hz, 1H), 7.13 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 3.71 (s, 3H), 3.25-3.40 (m, 2H), 2.82-2.93 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:25].[H][H]>C1COCC1.[Ni]>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH2:24])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:25]
Reactant: [H][H]
Reactant: N#CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: NCCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 65.9 %

Procedure:
A mixture of intermediate 14 (6 g) in THF (250 ml) was hydrogenated with Raney nickel (3 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent CH2Cl2/(CH3OH/NH3)90/10). The pure fractions were collected and the solvent was evaporated, yielding 4 g (68%) [1-(2-amino-ethyl)-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (intermediate 15).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -10 °C

Procedure:
5.1 g of the product from step C were dissolved in methanol (50 ml). The solution was cooled to −10° C. and treated with thionyl chloride (3 ml) and subsequently heated under reflux for 1 hour. The reaction mixture was evaporated and the residue dissolved in ether. The ether phase was washed with water, dried and evaporated to yield 5.1 g of a reddish brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[C:30]([NH2:34])(=[O:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:32][CH2:31][C:30]([NH2:34])=[O:33])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: C=CC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(N)=O)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
A solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), acrylamide (24 mg, 0.33 mmol) and DIEA (87 μL, 0.5 mmol) in NMP (1 mL) was stirred at 80° C. for 10 h. LCMS at this point shows the reaction was not complete, so additional acrylamide (2×36 mg) was added and the reaction continued until LCMS shows the reaction was complete. The crude product was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)propanamide as a white powder; ESMS m/z 483.2 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[O:23][CH:24]=1>>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:31]=[CH:32][C:27](/[CH:26]=[CH:25]/[C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:15][C:11]3[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)[CH:14]=[CH:13][CH:12]=3)[N:21]=2)=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1cccc(CCCn2ccnn2)c1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3cccc(CCCn4ccnn4)c3)co2)cc1
Yield: 90.2 %

Procedure:
Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (123 mg), 65% oily sodium hydride (24 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl)-1,3-oxazole (183 mg), the same reaction as Example 2 was carried out to yield the titled compound (248 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1cccc(OC)c1CN
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,6-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.