Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8](OC)=[O:9])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(Br)cc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of methyl 5-bromo-2-methyl-3-furancarboxylate (Example 49 (1)) (7.5 g) in tetrahydrofuran (30 mL) was added dropwise to a suspension of lithium aluminum hydride (1.9 g) in tetrahydrofuran (30 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give (5-bromo-2-methylfuran-3-yl)methanol (5.7 g, 60%) as an oil. A suspension of the obtained (5-bromo-2-methylfuran-3-yl)methanol (5.5 g) and manganese dioxide (15 g) in tetrahydrofuran (100 mL) was stirred at 40° C. for 2 days. Manganese dioxide was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.8 g, 51%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B(O)O.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]=1[CH3:11]
Reactant: Cc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1cc(N)ccc1Br
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1cc(N)ccc1-c1ccc(C(F)(F)F)cc1C

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromo-3-methoxyaniline and (2-methyl-4-(trifluoromethyl)phenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:13])[C:5]1[NH:10][C:9](=[O:11])[NH:8][C:7](=[O:12])[CH:6]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:13][N:4]1[C:5]2[N:10]([C:9](=[O:11])[NH:8][C:7](=[O:12])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: CN(CCO)c1cc(=O)[nH]c(=O)[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCn2c1cc(=O)[nH]c2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a suspension of 6-((2-hydroxyethyl)(methyl)amino)pyrimidine-2,4(1H,3H)-dione (0.463 g, 2.5 mmol) in tetrahydrofuran (310 ml) at rt was added Ph3P (1.967 g, 7.50 mmol), then DIAD (1.458 ml, 7.50 mmol) was added dropwise. The reaction mixture was stirred at rt for 3 h, and concentrated. The residue was partitioned between ethyl ether and water. The aqueous phase was separated, washed with ethyl ether again, and then concentrated to afford the title compound as a light-yellow solid (0.414 g, 99% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH:5]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>C(Cl)Cl.C(OCC)(=O)C.CCOCC>[ClH:27].[CH2:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:4][NH:3][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
9.8 g of 1-amino-4-(4-benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butane dihydrochloride and 6.7 g of triethylamine are dissolved in 200 ml of methylene chloride. 2.28 g of ethyl chloroformate are added dropwise to this solution at room temperature and the reaction mixture is left to stand for one hour at room temperature, with stirring. The reaction mixture is concentrated under vacuum and the residue is taken up in ethyl acetate/water and washed successively with a 5% solution of sodium hydroxide, water and a saturated solution of sodium chloride. The organic phase is dried over Na2SO4 and concentrated under vacuum to give a residue, which is chromatographed on silica gel using a 94/6 methylene chloride/methanol mixture as the eluent. Concentration of the pure fractions gives a residue, which is taken up in ethyl acetate. A solution of hydrogen chloride in ether is added to the ethyl acetate solution and the hydrochloride is filtered off.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C>[C:24]([CH2:23][CH2:22][CH2:21][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)#[N:25]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCN(c2ccccc2F)CC1
Yield: 98 %

Procedure:
2-Fluorophenyl piperazine (6.5 g) are suspended in acetonitrile (50 ml), anhydrous K2CO3 (1.5 eq) and 4-bromobutyronitrile (1.05 eq) in acetonitrile (25 mL) are added dropwise. The mixture is heated at reflux for 10 h and then filtered, the filtrate is concentrated in vacuo. The residue is taken up in AcOEt and washed three times with water. The organic layer is extracted with hydrochloric acid (1M) and the aqueous acid layer is washed with AcOEt and neutralized with aqueous ammonia (28% in H2O) to pH 11. The extraction is carried out with AcOEt and the organic layer is washed twice with water and dried over Na2SO4. The mixture is concentrated to give the title compound (8.35 g, 98%). 1H NMR (200 MHz, CDCl3) δ 1.80-1.90 (m, 2 H), 2.42-2.49 (m, 2H), 2.52-2.56 (m, 2H), 2.59-2.64 (m, 4H), 3.07-3.13 (m, 4H), 6.91-7.07 (m, 4H). RMN 13C (50 MHz, CDCl3): δ 14.8, 22.6, 50.4, 53.0, 56.2 115.8, 116.2 118.8, 119.7, 122.3, 122.5, 124.3, 124.4, 153.1, 158.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[OH:10].C1(C)C=CC=CC=1.C(OCC)(=O)C>CCCCCCC.[O-2].[Mn+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:10]
Reactant: COc1cccc(C(O)c2ccc(F)cc2F)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ccc(F)cc2F)c1
Yield: 58.3 %

Procedure:
Combine (2,4-difluoro-phenyl)-(3-methoxy-phenyl)-methanol (Compound 7) (89.2 g, 357 mmol), manganese oxide (96 g, 1.1 mol), and toluene (500 mL) and heat to reflux, under a nitrogen atmosphere for 2 hours. TLC (30% ethyl acetate in heptane) shows that the reaction is complete. Filter reaction mixture through celite® and concentrate. Purify by column chromatography using a graded solvent mixture of 10% dichloromethane in heptane to 50% dichloromethane in heptane to give an oil. Cool overnight to solidify, and triturate with pentane to give the title compound as a white solid (51.7 g, 58% Yield). NMR is consistent with the final, desired compound. mp=50° C.-52° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([CH3:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:16])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccccc2)cc1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Cc2ccccc2)ccc1O
Yield: 82.4 %

Procedure:
A mixture of 30.8 g of 4-benzyl-2-methyl-1-methoxybenzene with 50 ml of hydrobromic acid and 100 ml of acetic acid was refluxed with heating for 5 hours. This was left for cooling and neutralized with an aqueous sodium hydrogen-carbonate solution and was extracted twice with 100 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then was concentrated under reduced pressure. The resulting oily residue was chromatographed on a silica gel column (eluting solvent hexane : acetone=3 : 1 (v/v)) to obtain 23.7 g of 4-benzyl-2-methylphenol.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[CH:11]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cc(Br)c2occc2c1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(C(F)(F)F)cc2ccoc12
Yield: 43.3 %

Procedure:
Beginning with 1.1 gm (4.15 mMol) 5-trifluoromethyl-7-bromobenzofuran and 0.93 gm (4.57 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 0.70 gm (43%) of the desired compound were recovered as a yellow solid essentially as described in EXAMPLE 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH3:16])=[CH:4][C:3]=1[CH2:17][OH:18].CC1(C)N([O])C(C)(C)CCC1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH3:16])=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: Cc1cc(OCc2ccccc2)c(C)cc1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C)cc1C=O
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of 11.0 g (46 mmol) of 2,5-dimethyl-4-(phenylmethoxy)benzenemethanol (Example I), 0.4 g (0.05×46=2.3 mmol) of TEMPO (tetramethyl-1-piperidinyloxy, free radical) (Aldrich) and 0.2 g (2.3 mmol) of cuprous chloride in 150 mL of dimethylformamide is stirred vigorously under an atmosphere of oxygen (maintained by a balloon) at ambient temperature for 18 hours overnight. The heterogeneous mixture is (dark green) filtered through a pad of celite, washed with diethyl ether and the solvents are removed on a rotary evaporator. The residue is dissolved in diethyl ether and the solution is washed with 2×50 mL of 2N hydrochloric acid solution, brine, dried (magnesium sulfate) and evaporated leaving 10.7 g of a yellow viscous residue. Distillation of the product through a short path apparatus affords 10.3 g of a pale yellow distillate, bp 156°-8° C./0.50 (175°-180° C.) on standing the product crystallizes; mp 48°-49° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
TFA (568 mg, 4.98 mmol) was added to solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropanecarboxamide (20 mg, 0.050 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a pale yellow solid. 1H NMR: (400 MHz, CD3OD): δ 8.63 (s, 1H), 7.80 (m, 2H), 7.68 (d, 1H, J=9.2 Hz), 7.57 (m 2H), 7.49 (d, 1H, J=8.8 Hz), 1.85 (m, 1H), 1.03 (m, 2H), 0.92 (m, 2H); ESI-MS [M+H]+: 318.06.
Reaction SMILES: C(O[C@@H:5]1[C@@H:9](Br)[C@@H:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])(=O)C.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+].[Br-].[Br-].C([N+]1C=CC(C2C=C[N+](CCCCCCC)=CC=2)=CC=1)CCCCCC>C(Cl)Cl.O>[C:13]([O:12][CH2:11][C@H:8]1[O:7][C@@H:6]([N:16]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:25])[C:22]=3[N:23]=[CH:24]2)[CH:5]=[CH:9]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@H]1Br
Agent: CCCCCCC[n+]1ccc(-c2cc[n+](CCCCCCC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(N)ncnc32)O1
Yield: 82.9 %

Procedure:
To a solvent mixture of 35 ml of methylene chloride and 15 ml of water were added 500 mg (1.21 mmol) of 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine, 2.09 g (12.0 mmols) of Na2S2O4 and 995 mg (7.2 mmols) of K2CO3. The mixture was stirred for a while in an argon atmosphere. Then 308 mg (0.6 mmol) of N,N'-diheptyl-4,4'-bipyridinium dibromide was added and the mixture was stirred at 28° C. for 15 hours. Furthermore, 418 mg of Na2S2C4, 380 mg of K2CO3 and 185 mg (0.36 mmol) of N,N'-diheptyl-4,4'-bipyridinium dibromide were supplemented followed by stirring for 24 hours. To the mixture was added 50 ml of methylene chloride. The mixture was fractionated and the organic phase was dried over anhydrous magnesium sulfate. After filtering and concentration, the concentrate was purified by silica gel PTLC [Whatman PLK-5F, developed with ethyl acetate-methanol (8:1)] to give 276 mg (83%) of 5'-O-acetyl-2',3'-didehydro-2',3'-dideoxyadenosine.
Reaction SMILES: [NH2:1][C@H:2]1[C:6]2([CH2:8][CH2:7]2)[C:5](=O)[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>C1(C)C=CC=CC=1>[NH2:1][C@H:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1
Reactant: N[C@@H]1CN(Cc2ccccc2)C(=O)C12CC2
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: N[C@@H]1CN(Cc2ccccc2)CC12CC2
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
Specifically, 6.3 g of (S)-7-amino-4-oxo-5-benzyl-5-azaspiro[2.4]heptane prepared in Example 5 was added to 31.5 g of toluene and was stirred at 45° C. To the mixture was added dropwise a mixture of 10.9 g of 65% by weight solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene and 12.6 g of toluene at a temperature of 75° C. or lower within 5 minutes. After the completion of addition, the mixture was stirred at 75° C. for 30 minutes and was cooled to 5° C. or below. To the cooled mixture was added 124.4 g of 10% by weight hydrochloric acid at a temperature of 20° C. or lower, the mixture was then diluted with 56.7 g of toluene and was separated. To the aqueous layer was added dropwise 122.3 g of 20% by weight sodium hydroxide aqueous solution at a temperature of 20° C. or lower. The mixture was diluted with 113.4 g of toluene and was separated, and the toluene layer was fractionated. The aqueous layer was extracted with 75.6 g of toluene, and the toluene layer was fractionated. These toluene layers were added together, were concentrated under reduced pressure and thereby yielded 3.7 g of (S)-7-amino-5-benzyl-5-azaspiro[2.4]heptane.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[C:8]([NH:15][CH3:16])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25].[Cl-].[NH4+]>O1CCCC1>[C:1]([N:5]1[CH2:6][C:7]2[C:8](=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=2)[N:15]([CH3:16])[C:24]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(C(C)(C)C)C2
Temperature: 0 °C
Yield: 82.6 %

Procedure:
A mixture of 240 mg (1 mmol) of 5-tert.butylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.28 ml of triethylamine in 5 ml of tetrahydrofuran was added dropwise to an ice-cooled solution of 1 ml (1.92 mmol) of phosgene (20% solution in toluene) in 5 ml of tetrahydrofuran. After 1 hour 30 ml of saturated aqueous ammonium chloride and 20 ml of tetrahydrofuran were added to the resulting mixture. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and then evaporated to give 220 mg (83%) of 3-tert.butyl-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide (40 mg, 0.12 mmol) and diisopropylethylamine (0.1 mL, 0.59 mmol) in methylene chloride (1.0 mL) was added benzoyl chloride (15 uL, 0.13 mmol) and stirred at room temperature for 30 min. The crude reaction was purified by ISCO Companion (silica, (silica, 0-5% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-benzoylamino-ethyl)-amide (48 mg, 48%). LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.36 (1H, s) 8.55 (1H, s) 8.24 (1H, br. s.) 8.00 (1H, d, J=5.27 Hz) 7.73-7.85 (3H, m) 7.43-7.52 (2H, m) 7.35-7.42 (2H, m) 7.28 (1H, d, J=3.32 Hz) 6.82 (1H, d, J=5.47 Hz) 6.40 (1H, d, J=3.51 Hz) 3.39-3.45 (4H, m)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[CH2:28]([O:35][CH2:36][CH2:37]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][CH2:36][CH2:37][Br:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCCOCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCc1ccccc1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of triphenyl phosphine (2.1 g, 7.9 mmol) in dry methylene chloride (16 mL) was added dropwise over 10 min to a stirred mixture of N-bromosuccinimide (1.4 g, 7.9 mmol) in dry methylene chloride (23 mL) at -78° C. The reaction was kept in the dark and stirring was continued until all the N-bromosuccinimide had dissolved (10 min). A solution of 2-(benzyloxy)ethanol in dry methylene chloride (10 mL) was added dropwise. The cooling bath was removed and stirring was continued for 12 h at rt. The organic layer was then concentrated in vacuo and passed through a silica plug with 1:1 hexane:methylene chloride to afford 2-(benzyloxy)bromoethane (1.20 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:11][CH2:12][CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].C(=O)([O-])[O-:16].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]([OH:16])([CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(O)(C(=O)O)C(=O)OCC
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Air was bubbled for 1 hour at room temperature through a suspension of 15.0 g (72.7 mmol) diethylpropylmalonate and 47.6 g (145 mmol) cesium carbonate in 120 ml dimethylformamide. At 10-20° C. 150 ml water were added and stirring was continued at room temperature for 3 hours. Most of the dimethylformamide was then removed by vacuum distillation at 35° C. bath temperature. 1 l water was added and extraction with diethylether yielded 11.7 g 2-hydroxy-2-propyl-malonic acid monoethylester, MS (m/e): 189.1 (M−H)−.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:28][O:29][C:30]([CH:32]1[NH:37][CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([CH:32]1[N:37]([C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 2 °C
Reaction time: 0.25 h

Procedure:
A mixture of 16.7 g dicyclohexycarbodiimide, 10.9 g hydroxybenzotriazole hydrate, 17.2 g diphenylacetic acid and 150 mL acetonitrile is stirred at 2° C. for 15 min then treated with a solution of 25.4 g methyl-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate in 125 mL acetonitrile. The resulting suspension is stirred 48 hr at 25° C., filtered and the filtrate is evaporated, dissolved in dichloromethane, washed with 10% Na2CO3, dried and evaporated. Chromatography on silica gel (chloroform-methanol, 99:1) gives a crisp foam which crystallizes when triturated with methanol. MS (FAB) 525 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([OH:10])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cl:18][C:19]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][CH3:43])[CH:37]=2)[C:22]2[N:23]=[CH:24][N:25]=[C:26]([NH:27]C(=O)OC(C)(C)C)[C:21]=2[C:20]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1.C(O)(C(F)(F)F)=O>CC#N.CN(C=O)C>[NH2:27][C:26]1[C:21]2[C:20]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)=[C:19]([Cl:18])[N:35]([C:36]3[CH:37]=[C:38]([N:42]([CH3:43])[C:8](=[O:10])/[CH:7]=[CH:6]/[CH2:5][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:11])[CH:39]=[CH:40][CH:41]=3)[C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: CN(C/C=C/C(=O)O)C1CC1
Reactant: CNc1cccc(-n2c(Cl)c(-c3ccc(Cl)cc3)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C(=O)/C=C/CN(C)C1CC1)c1cccc(-n2c(Cl)c(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A suspension of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (110 mg, 0.34 mmol) in dry MeCN (5.0 mL) was cooled to 0° C. Oxalyl chloride (0.5 mL, 0.69 mmol) and one drop of DMF were added, respectively. The resulting mixture was stirred at 0° C. for 2 hrs. After the suspension was gradually turned into a clear solution, the solvents were removed under reduced pressure (below 35° C.). Dry DCM (5.0 mL) was added and evaporated to remove excess oxalyl chloride. The freshly generated acid chloride was dissolved in dry DCM (5.0 mL) was added dropwise to a solution of tert-butyl 6-chloro-5-(4-chlorophenyl)-7-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (22) (81 mg, 0.18 mmol). After the resulting mixture was stirred at r.t. for 1 hr, TFA (2.0 mL) was introduced. Stirring was continued for 30 min before it was finally quenched with MeOH (1.0 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3H2O)) to afford (E)-N-(3-(4-amino-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide (23) (34 mg, 39% yield) as a white solid. LC-MS (ESI): m/z (M/M+2) 521.2/523.1. 1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.53-7.43 (m, 5H), 6.75-6.63 (m, 1H), 6.24 (br, 1H), 6.09-5.96 (m, 1H), 3.29 (s, 3H), 3.11 (d, J=6.2 Hz, 2H), 2.10 (s, 3H), 1.63-1.54 (m, 1H), 0.38-0.26 (m, 2H), 0.25-0.15 (m, 2H).