Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][N:6]([CH:9]2[O:13][CH:12]([CH2:14][O:15][C:16](=[O:22])[CH:17]([NH2:21])[CH:18]([CH3:20])C)[CH:11]([OH:23])[CH:10]2[OH:24])[C:5](=[O:25])[N:4]=1.Cl.NC1C=CN([CH:34]2O[CH:37]([CH2:39]OC(=O)C(N)C)[CH:36](O)[CH:35]2O)C(=O)N=1>>[ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][N:6]([CH:9]2[O:13][CH:12]([CH2:14][O:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][C:20]3[CH:39]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:11]([OH:23])[CH:10]2[OH:24])[C:5](=[O:25])[N:4]=1
Reactant: CC(N)C(=O)OCC1OC(n2ccc(N)nc2=O)C(O)C1O
Reactant: CC(C)C(N)C(=O)OCC1OC(n2ccc(N)nc2=O)C(O)C1O
Agent: Cl
Product: Nc1ccn(C2OC(COC(=O)C(N)Cc3ccccc3)C(O)C2O)c(=O)n1

Procedure:
In similar fashion substituting boc-L-valine and boc-L-alanine there was obtained respectively, 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl ester hydrochloride (compound 18; MH+=384; MNa+=406) and 2-amino-propionic acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl ester hydrochloride (compound 20; MH+=356; MNa+=378).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:43]=[CH:42][C:35]([C:36]([NH:38][CH:39]2[CH2:41][CH2:40]2)=[O:37])=[C:34]([F:44])[CH:33]=1>>[CH:39]1([NH:38][C:36]([C:35]2[CH:42]=[CH:43][C:32]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[N:14][C:13]=4[CH:29]=3)=[CH:33][C:34]=2[F:44])=[O:37])[CH2:41][CH2:40]1
Reactant: O=C(NC1CC1)c1ccc(Br)cc1F
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(=O)NC5CC5)c(F)c4)ccc3o2)CC1
Yield: 7 %

Procedure:
Following the General Procedure-3, the titled compound (20 mg) was prepared from Intermediate 14 (250 mg, 0.61 mmol) and 4-bromo-N-cyclopropyl-2-fluorobenzamide (156 mg, 0.61 mmol) as an off-white solid. M.P.: 162-165° C. MS (m/z): 466.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccccc2Cl)cc1
Yield: 73.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(2-chlorophenyl)ethanol (prepared as described in Preparation 11), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.3 g of sodium cyanoborohydride, 3.25 g of the title compound were obtained having an Rf=0.39 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11](SC)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11]([NH:47][C:46]3[CH:45]=[CH:44][C:43]([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)=[CH:49][CH:48]=3)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: CSc1ncc2c(=O)n(C)nc(C)c2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 1C (100 mg, 0.450 mmol) in dichloromethane (1.5 mL) was added meta-chloroperoxybenzoic acid (122 mg, 0.495 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (157 μl, 0.900 mmol) and 4-(4-methylpiperazin-1-yl)aniline (86 mg, 0.450 mmol) were added to the solution, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure. The crude residue was purified by RP-MPLC (125 g C-18 silica gel), eluting with a gradient of 5 to 50% acetonitrile in water each containing 0.1% TFA, to provide the title compound. MS ESI(+) m/z 366.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ ppm 10.33 (s, 1H), 9.22 (s, 1H), 7.77-7.62 (m, 2H), 6.99-6.91 (m, 2H), 3.63 (s, 3H), 3.20-3.02 (m, 4H), 2.46-2.43 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)([CH2:3][CH3:4])[CH3:2].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:37]([CH3:40])([O-:39])=[O:38]>>[N+:37]([CH2:40][C@@:9]1([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][C@H:7]2[C@@H:10]1[CH:11]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:6]2)([O-:39])=[O:38]
Reactant: C[N+](=O)[O-]
Reactant: CCC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C)C1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Tert-butyl(±)-[(1S,5R)-3-sec-butylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (3.10 g, 11.8 mmol) was dissolved in nitromethane (30 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.20 g, 14.5 mmol) was added, and the mixture was stirred at 60° C. for 5 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the compound of interest as a yellow oil substance (3.28 g, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH2:17][C:18]1[C:19]([CH3:34])=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 3-{3-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[H-].[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:34][C:31]1[CH:30]=[N:29][C:28]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:13])=[O:14])[C:6]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:33][CH:32]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (115 mg) was dissolved in THF (15 ml). Sodium hydride (60 mg) was added followed by stirring for 15 min at 50° C. Then 2-chloro-5-bromo-pyrimidine (135 mg) was added and stirring was continued for 8 h at 75° C. The reaction mixture was poured onto ice water, acidified with solid citric acid and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and the solvent was evaporated. The crude material was purified by plate chromatography with diethyl ether to give n-propanesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (65 mg) as a white powder. LC-MS: tR: 4.91, [M+H]+: 510.13.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13].C1(P(=C=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCOc1cc(C=O)ccc1O
Reactant: COC(=O)C=C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCOc1cc(/C=C/C(=O)OC)ccc1O
Yield: 78.2 %

Procedure:
The preparation is carried out analogously to Example 2 from 0.76 g (4.22 mmol) of 4-hydroxy-3-propoxybenzaldehyde and 1.48 g (4.43 mmol) of methyl (triphenylphosphoranylidene)acrylate and gave 0.78 g of methyl (E)-4-hydroxy-3-propoxycinnamate.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:14][CH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C1COCC1>[CH2:3]([N:10]1[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[O:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCN(CCc1cccnc1Cl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCOc3ncccc3CC2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.7 %

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (60% in oil, 0.24 g) in THF (5 mL) was added a solution of the compound (0.88 g) obtained in step 6 in THF (10 mL) at 0° C., and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was cooled to 10° C., and poured into water. The resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 20→33% ethyl acetate/hexane) to give the title compound (0.59 g, 77%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:21][C:15]3[N:16]=[CH:17][N:18]=[C:19](O)[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:19]1[C:14]2[CH:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[NH:21][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
Analogously to Step 8.3,1.45 g of 6-(4-ethoxycarbonyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol in 15 ml of phosphorus oxychloride are heated under a protective gas for 2 hours and worked up, yielding the title compound; m.p.: 250° C. (decomp.): TLC-Rf =0.63 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =302.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[C:27]([CH3:33])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[C:27]([CH3:33])[N:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cn3)CC2)nc1C
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)nc2)C1=O
Yield: 53.2 %

Procedure:
Using 1-acetyl-2-imidazolidinone (655 mg) and (5-bromopyridin-2-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (1.81 g) described in Preparation Example 147 and by the reaction and treatment in the same manner as in Example 1, the title compound (1.08 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2.[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(C#N)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2cc(CBr)ccc2c1
Yield: 78.6 %

Procedure:
6.11 g of 6-methyl-2-naphthalenecarbonitrile was dissolved in 100 ml of carbon tetrachloride, and the solution was mixed with 6.63 g of N-bromosuccinimide and 30 mg of 2,2-azobis-iso-butylonitrile. After refluxing under heating for 4 hours, the resulting reaction solution was mixed with chloroform, washed with water, and then dried. By distilling off the solvent, 7.07 g of colorless 6-bromomethyl-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH2:28]([Cl:30])Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[N:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:28]([Cl:30])=[CH:12][CH:13]=3)[C:3]=12
Reactant: ClCCl
Reactant: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)nc1
Yield: 291.6 %

Procedure:
To a suspension of (E)-N-(6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) pyridine-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (65) (100 mg, 0.21 mmol), arylboronic acid (0.27 mmol) and K3PO4.3H2O (168 mg, 0.63 mmol) in DME (8 mL) and water (2 mL) was added Pd(dppf)Cl2.DCM (9 mg, 0.02 mmol). The resulting mixture was purged with N2 (3×) before microwaved at 90° C. for 45 min. The solvents were evaporated and the residual was directly loaded to a silica gel column and pre-purified by column chromatography (0 to 10% MeOH in DCM) followed by preparative HPLC purification (RP C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(6-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (66) (27 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.82 (br, 2H), 8.57 (d, J=2.5 Hz, 1H), 8.40 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.08 (dd, J=8.7, 2.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 6.73-6.65 (m, 1H), 6.34-6.19 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 2.69 (s, 6H). LC-MS (ESI): m/z (M/M+2) 463/465.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.[SH:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)c2ccc(SCCO)cc2)cc1C
Reaction time: 6 h

Procedure:
12.2 g (0.05 mol) of 4'-chloro-3,4-dimethylbenzophenone and 4.3 g (0.055 mol) of 2-mercaptoethanol in 50 ml of dimethylacetamide are heated to 95° under nitrogen. 13.8 g (0.1 mol) of calcined K2CO3 are then added. The suspension is kept at 90°-100° C. for 6 hours. 100 ml of water are poured over the resulting reaction mixture and the mixture is extracted with ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The crystals obtained are recrystallised from methanol and dried in vacuo at 60° C. Yield: 10.1 g (71%). Melting point 92°-93° C.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[O:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([NH:18][C:19]2[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]([NH:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[NH:36][C:37](=O)OC(C)(C)C)[N:20]=2)[CH2:10][CH2:9]1>>[O:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([N:18]2[CH:1]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:28]2[C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[N:36]=[CH:37]2)=[N:22][CH:23]=3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3ccccc32)n1
Reactant: O=C(O)C(F)(F)F
Product: Fc1ccc2ncn(-c3ncc4ncn([C@@H]5CCOc6ccccc65)c4n3)c2c1

Procedure:
The title compound as a TFA salt was synthesized from (R)-tert-butyl 2-(4-(chroman-4-ylamino)-5-nitropyrimidin-2-ylamino)-4-fluorophenylcarbamate via the procedure described in Example 15. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 2H), 8.27 (dd, 1H), 7.89 (s, 1H), 7.78 (dd, 1H), 7.32 (td, 1H), 7.32 (td, 1H), 7.13 (td, 1H), 7.1-6.9 (m, 3H), 6.00 (t, 1H), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 2.7-2.5 (m, 2H). 19F NMR: δ −116.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(OCCCOc2ccc(Cl)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 65.7 %

Procedure:
A mixture of 33.5 g of methyl{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate and 19.6 g of N-bromosuccinimide in 400 ml of carbon tetrachloride is refluxed for 24 hours or until the reaction is complete. The mixture is cooled, filtered and the filtrate passed through a column of silica gel with carbon tetrachloride as eluent to give 27.2 g of product as an oil. Crystallization from petroleum ether gives white crystals, mp 49°-53° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:26]([CH3:27])[CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CNC1CCN(C)CC1
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde was reacted with 1-methyl-4-(methylamino)piperidine using the general reductive amination procedure to yield (2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine, which was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester in General Procedure A. Purification on silica yielded 393 NMR: (CDCl3): 1.61-1.64 (2H, m), 1.79-1.86 (2H, m), 1.91-1.96 (2H, m), 2.27 (3H, s), 2.31 (3H, s), 2.48-2.52 (1H, m), 2.92 (2H, d), 3.81 (2H, s), 3.85-3.89 (4H, m), 3.92-3.96 (4H, m), 5.23 (2H, s, br.), 7.12 (1H, s), 9.30 (2H, s). MS ESI m/z 455 (MH+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1nc2ccc(O)cn2n1)C1CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn2n1)C1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.8 %

Procedure:
To a solution of N-(6-hydroxy[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (2 g, 9.16 mmol) and 1,2-difluoro-4-nitrobenzene (1.46 g, 9.16 mmol) in dimethyl sulfoxide (20 mL) was added cesium carbonate (4.48 g, 13.7 mmol), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was filtered through celite, and the filtrate was diluted with water and ethyl acetate, and extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (1.5 g, 46%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:9]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:8]=3[N:7]=2)[CH2:2]1.C(N(CC)CC)C.Br[CH2:31][CH2:32][OH:33]>>[NH2:17][C:13]1[N:12]=[C:11]([N:10]2[C:9]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:5][CH:3]2[CH2:2][N:1]([CH2:31][CH2:32][OH:33])[CH2:4]2)[CH:16]=[CH:15][N:14]=1
Reactant: OCCBr
Reactant: Nc1nccc(-n2c(OC3CNC3)nc3ccc(Br)cc32)n1
Solvent: CCN(CC)CC
Product: Nc1nccc(-n2c(OC3CN(CCO)C3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A mixture of 4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (2 g, 0.44 mmol, 8% purity) and triethylamine (1.5 mL) in 2-bromoethan-1-ol (1.5 mL) was stirred at room temperature for 12 h. The reaction mixture was purified on a C18 column (water/acetonitrile, 5:95-80:20) to yield 100 mg (50%) of 2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-ol as a yellow solid: LC-MS: m/z=+405 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][Cl:21])=[O:16].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:20][CH2:19][CH2:18][O:17][C:15]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: O=C(Cl)OCCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCCCCl)N1CCN(C(=O)C2CCCO2)CC1
Reaction time: 2 h

Procedure:
To a 0° C. solution of 1-(tetrahydrofuran-2-ylcarbonyl)piperazine (202 mg, 1.1 mmol) in dichloromethane (5 mL) was added 3-chloropropyl chloroformate (133 μL, 1.1 mmol) followed by N,N-diisopropylethylamine (192 μL, 1.1 mmol). The reaction was allowed to reach room temperature over 2 h, at which time the reaction was evaporated to yield the title compound as a wheat colored oil that was used without further purification.