Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45](O)=[O:46])=[CH:41][CH:40]=2)[S:33]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:43][CH2:44][C:45]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:46])=[CH:48][CH:49]=2)[S:33]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 72.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (1.66 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.99 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11][CH:10]=2)[O:3]1.B.CO>C1COCC1>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)c3ccccc23)OC1(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(CO)c3ccccc23)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoic acid (2.5 g, 8.39 mmol) was dissolved in anhydrous THF. The solution was cooled down in an ice-water bath. Borane solution (1.00M in THF, 25 ml, 25 mmol) was added dropwise. After addition, the reaction was stirred at room temperature for 4 hours. Methanol (20 ml) was added with ice-water batch to quench the reaction until no gas was produced. The solvent was evaporated, and the residue was extracted with ethyl acetate/water to give the product as a white solid (1.79 g, 75%). 1H NMR (300 MHz, CD2Cl2, δ): 8.80 (m, 1H), 8.10 (m, 1H), 8.04 (m, 1H), 7.57 (m, 3H), 5.18 (s, 2H), 1.43 (s, 12H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH3:14]>CC(O)C>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: N
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Product: Nc1c([N+](=O)[O-])cnc2ccsc12
Yield: 99 %

Procedure:
To a suspension of 2.55 g of 7-chloro-6-nitrothieno[3,2-b]pyridine 15 in 130 ml of 2-propanol is introduced excess anhydrous ammonia at 45° C. (bath temperature) during 4 hours and the mixture is evaporated in vacuo. The residue is suspended in water, collected by filtration, and then washed with water and ether to give 2.30 g (99%) of Compound 16. An analytical sample is recrystallized from chloroform methanol, affording yellow crystals melting at 266°-268.5° C.
Reaction SMILES: C(OCC)C.BrBr.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15][C:16]1[CH:17]=[C:18]2[C:28](=[CH:29][CH:30]=1)[O:27][C:21]1[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2=[O:31]>[Zn].C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:28](=[CH:29][CH:30]=1)[O:27][C:21]1[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:19]2([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:31]
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: CCOC(=O)CBr
Agent: BrBr
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 104.2 %

Procedure:
A 3-neck RBF equipped with an addition funnel and reflux condenser was charged with zinc dust (37.9 g, 580 mmol) and diethyl ether (300 ml). Bromine (1.544 ml, 29.0 mmol) was added drop wise to the stirring suspension at RT. After 5 minutes, ethyl 2-bromoacetate (32.3 ml, 290 mmol) was added drop wise via addition funnel over the time period of 1 hour. The reaction mixture was heated to reflux for one hour. 7-Bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (30 g, 97 mmol) was added in one portion followed by THF (200 ml). After stirring at 40° C. for 10 minutes, the reaction mixture was cooled to RT and quenched with saturated aqueous ammonium chloride solution (250 mL). The reaction mixture was stirred for 1 hour before diluting with EtOAc and filtering through a pad of celite. The organic layer was separated, washed with brine and dried over MgSO4. The solution was concentrated under reduced pressure to afford ethyl 2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.3 g) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[C:8](OC(=N)N(C(C)C)C(C)C)([CH3:11])([CH3:10])[CH3:9]>C(Cl)(Cl)Cl>[Br:1][C@H:2]([CH2:6][OH:7])[C:3]([O:5][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:4]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: O=C(O)[C@H](Br)CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H](Br)CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
18.1 g of (2R)-2-bromo-3-hydroxypropionic acid and 200 ml of chloroform were mixed, and 53.6 g of O-tert-butyl-N,N-diisopropylisourea was added under cooling with ice, followed by stirring at room temperature for 15 hours. Insoluble matters were filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 14.7 g (yield: 61%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=O)[CH2:10][C:4]2=[N:3][N:2]=1.CO>O1CCCC1>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: O=C1Cc2nncn2-c2ccccc2N1
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCc1nncn1-2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g of 5,6-dihydro-4H-[1,2,4]triazolo-[4,3-a][1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10 M boranedimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted with dichloromethane. The extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.
Reaction SMILES: O1[C:5]2([CH2:14][CH2:13][C:8]3([CH2:12][CH2:11][NH:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CO>[CH2:9]1[C:8]2([CH2:13][CH2:14][C:5](=[O:4])[CH2:6][CH2:7]2)[CH2:12][CH2:11][NH:10]1
Reactant: C1CC2(CCC3(CC2)OCCO3)CN1
Agent: Cl
Solvent: CO
Product: O=C1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecane (10 g, 50.69 mmol) in MeOH (100 mL) was added HCl aqueous solution (2 M, 30 mL, 60 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (100 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/7) to give the title compound as a yellow solid (10 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6]1[C:7]2[CH:15]=[CH:14][NH:13][C:8]=2[N:9]=[C:10](Cl)[N:11]=1.[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6]1[C:7]2[CH:15]=[CH:14][NH:13][C:8]=2[N:9]=[C:10]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[N:11]=1
Reactant: CC(C)(CN)CNc1nc(Cl)nc2[nH]ccc12
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(C)(CN)CNc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]ccc12
Temperature: 116 °C
Yield: 15.3 %

Procedure:
A mixture of N-(3-amino-2,2-dimethylpropyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 0.28 mmol), 6-aminoindazole (93 mg, 0.70 mmol) and trimethylsilyl chloride (0.100 mL, 0.72 mmol) in nBuOH (2 mL) was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (15 mg). MS 351.4 (M+H); UV 206.1, 242.6, 304.3 nm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromopyridine (1.00 g) in toluene (10 mL) and ethanol (5 mL) was added phenylboronic acid (515 mg), sodium carbonate (1.34 g) and tetrakis (triphenylphosphine)palladium(0) (24 mg) and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted into ethylacetate (2×30 mL). The organic layers were washed with brine (40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 5-bromo-2-phenyl-pyridine as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]([CH3:19])=[CH2:18].C(=O)([O-])O.[Na+].O>C(Cl)Cl>[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]1([CH3:19])[CH2:18][O:9]1
Reactant: C=C(C)COCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCOCC1(C)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
m-Chloroperbenzoic acid (22.7 g, 92 mmol) was gradually added to a solution of 3-methoxymethoxy-2-methyl-1-propene (9.7 g, 84 mmol) prepared in Reference Example 176 in methylene chloride (200 ml) while cooling in an ice-bath and the mixture was stirred at room temperature for 6 hours. Sodium hydrogencarbonate (14.1 g, 168 mmol), water and methylene chloride were added to the reaction mixture, which was stirred for a while. The organic layer was separated, washed with sodium hydrogencarbonate aqueous solution, sodium thiosulfate aqueous solution and then sodium hydrogencarbonate aqueous solution, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-2-methyloxirane (6.8 g, yield 62%) as a green-colored oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([CH2:19][CH:20]3[CH2:24][CH2:23][N:22]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:21]3=[O:31])=[C:14]([Cl:32])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CCOC(C)=O.Cl>O1CCOCC1>[Cl:32][C:14]1[CH:13]=[C:12]([C:9]2[S:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][CH:10]=2)[CH:17]=[C:16]([Cl:18])[C:15]=1[CH2:19][CH:20]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:21]1=[O:31]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Add 1.0 mL of LiOH (2.0 N aq.) to a solution of 5-[3,5-Dichloro-4-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester (85 mg, 0.182 mmol) in 3.0 mL of dioxane and heat to 50° C. After 3 hours, a TLC shows the reaction to be complete. Dilute the reaction with DCM /H2O (50/50), acidify with 1.0N HCl, extract with ethyl acetate, and dry the combined organic layers with sodium sulfate. Filter off the sodium sulfate and concentrate to give the title compound. LC/MS (API) m/z: 452.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=2)[CH:7]=1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:21][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=3[O:17][CH3:16])=[O:13])=[CH:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Solvent: Cc1ccccc1
Product: COc1ccc(CNC(=O)c2cnc3ccc(Br)cn23)c(OC)c1
Temperature: 120 °C
Yield: 20 %

Procedure:
To a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol) in toluene (5 mL) was added 2,4-dimethoxybenzylamine (0.93 g, 5.6 mmol). The reaction mixture was heated at 120° C. for 2 days in a sealed tube, allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient of ethyl acetate in hexanes to afford 6-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,2-a]pyridine-3-carboxamide as a yellow oil in 20% yield (0.29 g): 1H NMR (300 MHz, CDCl3) δ9.70-9.67 (m, 1H), 7.91 (s, 1H), 7.53 (dd, J=9.5, 0.7 Hz, 1H), 7.38 (dd, J=9.5, 1.9 Hz, 1H), 7.27-7.21 (m, 2H), 6.48-6.38 (m, 2H), 4.54 (d, J=5.8 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H); MS (ES+) m/z 389.8 (M+1), 391.8 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Clc1ccc2c(c1)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(Cl)ccc21
Yield: 68.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 5-chloroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 255 mg of 2-[2-(5-chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[C:21]=S.C(Cl)CCl>CC#N>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:21]([NH:20][C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=4)=[N:19][C:14]=3[CH:13]=2)=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: Nc1ccc(Oc2ccnc3ccccc23)cc1N
Solvent: CC#N
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(Nc2nc3cc(Oc4ccnc5ccccc45)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(quinolin-4-yloxy)-benzene-1,2-diamine (Step B, 227 mg) in CH3CN (60 mL) was added over 5 min, a solution of 1-isothiocyanato-4-trifluoromethyl-benzene (183 mg) in CH3CN 10 mL). The mixture was stirred for 12 h at RT and EDC (260 mg) was added, followed by CH3CN (30 mL). The resulting mixture was heated at 80° C. for 2 h, then cooled to RT. The solvent was evaporated and the residue was dissolved in EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography in EtOAc to give an orange-brown solid. MS (MH+)=420.9, MW: 420.18 Calc'd for: C23H15F3N4O.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1[CH3:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1[CH3:28]
Reactant: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)c2ccc(O)cc2C)cc1C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of 4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoic acid methyl ester (1.0 g, 2.1 mmol) in THF (20.0 mL) is added 1.0 M TBAF/THF (3.2 mL, 3.2 mmol) at room temperature. The reaction mixture is stirred for 1.0 h. The reaction mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give the title compound as oil (0.45 g, 62%). LC-ES/MS: 300.3 (M+1), 298.3 (M−1).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O)(=S)[CH3:2].C([O-])(=O)C.[Na+].Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][C:28]=1[CH3:35]>O1CCOCC1.C(O)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)=[N:4][C:1]([CH3:2])=[N:34]2)=[CH:29][C:28]=1[CH3:35]
Reactant: CC(=S)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(NN)ccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(Cl)c(C)c2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The product from step A (3.09 g, 10.79 mmol), sodium acetate (0.879, 10.7 mmol) and (4-chloro-3-methylphenyl)hydrazine hydrochloride (2.24 g, 11.6 mmol) were mixed in dioxane (25 mL) and acetic acid (25 mL). The reaction mixture was warmed at 90° C. with stirring for 16 h, cooled to rt and the volatiles were removed. Purification of the residue on SiO2 (5 to 60% ethyl acetate, hexanes) afforded the title compound, which was used without further purification. HPLC/MS: 335.0, 337.0 (M-55), Rt=3.40 (LC4).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:11][O:12][C:13](Cl)=[O:14].Cl>O>[CH3:11][O:12][C:13]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of (S)-2-amino-3-methyl-butyric acid (10 g, 85 mmol), NaOH (10.3 g, 255 mmol) in water (100 mL) was treated with methylchloridocarbonate (8 g, 85 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and then 5 N aqueous HCl was added to the reaction mixture to adjust pH to 4. The mixture was filtered through a pad of Celite to give the product (10 g, 67% yield) as a white solid. 1H NMR (CH3OD, 400 MHz) δ (ppm) 4.05 (d, 1H), 3.65 (s, 3H), 2.14 (m, 1H), 0.95 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[C:8](=[N:10]O)[CH3:9].[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:14]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:12][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9]
Reactant: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(Cl)cc32)cc1
Yield: 78.1 %

Procedure:
A mixture of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime (514 mg, 1.41 mmol), Zn power (4.6 g, 70.64 mmol), NH4Cl (1.5 g, 28.26 mmol) in MeOH (20 mL) and HOAc (4 mL) was heated at reflux overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was diluted with CH2Cl2 (200 mL) and aqueous ammonia (20 mL). The organic layer was separated, washed with H2O, dried (NaSO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with MeOH—CH2Cl2 (1:15) to afford 385 mg (78%) of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine as yellow oil. MS (ESI): m/z=350.0 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=[O:4].O.C(O)(=O)/C=C\C(O)=O.[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:52]=1)[O:23][CH2:24][C:25]1[CH:51]=[CH:50][CH:49]=[CH:48][C:26]=1/[C:27]/2=[CH:28]\[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([C@@H:39]3[C@@H:43]([OH:44])[CH2:42][N:41]([CH3:45])[CH2:40]3)/[C:34](=[N:36]/[C:37]#[N:38])/[NH:35][C:31]=2[CH:30]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:22]([CH:52]=1)[O:23][CH2:24][C:25]1[CH:51]=[CH:50][CH:49]=[CH:48][C:26]=1/[C:27]/2=[CH:28]\[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([C@@H:39]3[C@@H:43]([OH:44])[CH2:42][N:41]([CH3:45])[CH2:40]3)/[C:34](=[N:36]/[C:37]([NH2:38])=[O:4])/[NH:35][C:31]=2[CH:30]=1
Reactant: CN1C[C@H](O)[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C[C@H](O)[C@@H](n2/c(=N/C(N)=O)[nH]c3cc(/C=C4\c5ccccc5COc5cc(F)ccc54)ccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a mixture of trifluoroacetic acid (30 mL) and water (6.0 eq, 100 mmol, 1.81 mL) in an ice bath add (E)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-1-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide maleate (16.73 mmol, 10.00 g). Allow the resulting suspension to warm up to room temperature and stir for 2 h. Dilute the solution with ethyl acetate (250 mL), cool the mixture in an ice bath for 30 min, and treat with 5 N sodium hydroxide to pH=11. Wash the organic layer with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography eluting with 2.5 to 5% methanol in ethyl acetate to obtain a white solid. Dry in a vacuum oven at 40° C. overnight to obtain the title compound (6.74 g, 81%). LC-MS m/z 500.2 [M+H]+.
Reaction SMILES: C(N1CCN(C2C=CC([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=3)=CC=2)CC1)C1C=CC=CC=1.[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH:34][C:23]3[N:22]=[C:21]([NH2:20])[C:26]([F:27])=[CH:25][N:24]=3)=[CH:32][C:31]=2[O:30]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Product: Nc1nc(Nc2ccc3c(c2)OCCO3)ncc1F
Yield: 127.1 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N4-[4-(N-benzylpiperazino)phenyl)]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDCl3): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H, NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28–7.36 (m, 5H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.66; LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH+).