Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#[N:19].[Na+].CCN(CC)CC.[CH3:28][C:29]([O:32][C:33]([O:35]C(OC(C)(C)C)=O)=O)([CH3:31])[CH3:30]>CO.O>[C:29]([O:32][C:33](=[O:35])[NH:19][CH:15]1[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14]2)([CH3:31])([CH3:30])[CH3:28]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-benzyl-3-aza-bicyclo[3.2.1]octan-8-one (0.560 g, 2.60 mmol) (Lowe, J. A. et al. J. Med. Chem. 1994, 37, 2831-2840), NH4OAc (2.3 g, 30 mmol) and NaBH3CN (0.245 g, 3.90 mmol) in MeOH (15 mL) was stirred and heated at reflux for 72 h. The mixture was cooled to room temperature, and the solvent was removed. Aqueous NaOH (1 N, 10 mL) was added, and the aqueous suspension was extracted with CH2Cl2 (3×30 mL). The combined extract was washed with water (30 mL) and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was dissolved in dry CH2Cl2 (30 mL). Et3N (3 mL) and Boc2O (0.872 g, 4.00 mmol) were added, and the mixture was stirred for 16 h. Water (30 mL) was then added, and the mixture was extracted with CH2Cl2 (4×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (1:1 CH2Cl2/hexanes), affording an impure solid mainly containing (3-benzyl-3-aza-bicyclo[3.2.1]oct-8-yl)-carbamic acid tert-butyl ester. A mixture of the solid and Pd/C (10% in wt, 0.20 g, 0.188 mmol) in MeOH/EtOAc (40 mL, 3:1) was stirred under H2 atmosphere (1 atm) overnight. CH2Cl2 (20 mL) was then added, and the mixture was filtered through a celite cake. The filtrate was concentrated by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:1 CH2Cl2/MeOH/NH4OH), affording (3-aza-bicyclo[3.2.1]oct-8-yl)-carbamic acid tert-butyl ester as a white solid (0.277 g, 50%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.62-1.68 (m, 2H), 1.81-1.85 (m, 2H), 2.02 (s, br. 2H), 2.49-2.55 (m, 2H), 2.96-3.01 (m, 2H), 3.67-3.80 (m, 1H), 5.04 (s, br. 1H).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:20][CH:21]([CH3:25])[CH2:22][CH:23]=[O:24]>O1CCCC1>[OH:24][CH:23]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[CH2:22][CH:21]([CH3:25])[CH3:20]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)CC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of ethyl 4-iodobenzoate (20 g, 72 mmol) in tetrahydrofuran (200 mL) at −40° C. was added isopropylmagnesium chloride lithium chloride (62 mL, 80 mmol, 1.3 M in THF) dropwise, maintaining the internal temperature below −30° C. The mixture was stirred for 30 minutes and 3-methylbutanal (8.68 g, 101 mmol) was then added dropwise, maintaining the internal temperature below −35° C. Following the addition, the reaction was allowed to stir for 15 minutes at −35° C. and was then allowed to warm to room temperature. The reaction was quenched with 1 N aqueous hydrochloric acid (400 mL), and the mixture was extracted with ethyl acetate (2×200 mL). The organics were washed with brine (200 mL) and water (200 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-hydroxy-3-methylbutyl)benzoate (16 g, 93%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.95 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.73-4.76 (m, 1H), 4.28-4.33 (m, 2H), 1.60-1.71 (m, 2H), 1.41-1.46 (m, 1H), 1.31-1.39 (m, 3H), 0.87-0.92 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:25][CH:26]([CH3:28])[CH3:27])=[C:13]([C:15]2[NH:24][C:18]3=[N+:19]([O-])[CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([N:31](CC)CC)C.C[Si](C#N)(C)C>C(#N)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:25][CH:26]([CH3:28])[CH3:27])=[C:13]([C:15]2[NH:24][C:18]3=[N:19][C:20]([C:29]#[N:31])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc[n+]([O-])c2[nH]1
Agent: C[Si](C)(C)C#N
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(C#N)nc2[nH]1
Yield: 69 %

Procedure:
A solution (10 ml) of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine 4-oxide, triethylamine (0.11 g) and trimethylsilyl cyanide (0.22 g) in acetonitrile was heated under reflux for 5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (0.15 g, yield 69%) as colorless crystals. melting point 214-215° C. purity 93%. M+H: 385. 1H NMR (CDCl3) δ: 1.53 (6H, d, J=6.0 Hz), 4.77-4.85 (1H, m), 5.16 (2H, s), 7.06 (1H, d, J=9.0 Hz), 7.12-7.18 (1H, m), 7.32-7.50 (5H, m), 7.66 (1H, d, J=8.1 Hz), 8.12 (1H, d, J=8.1 Hz), 8.20 (1H, d, J=3.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].C([Sn]([N:52]=[N+:53]=[N-:54])(CCCC)CCCC)CCC.C(O)(C(F)(F)F)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:54][N:53]=[N:52][N:14]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2nnn[nH]2)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid ethyl ester from above (0.260 g, 0.51 mmol) and tributyltin azide (4 equiv., 2.0 mmol, 0.650 g) were dissolved in DMSO (2 mL) and the solution stirred at 80° C. for 48 h. The reaction was then quenched with 1 N HCl (10 mL) and stirred for an additional 40 min. The aqueous phase was decanted and the oily residue dissolved in DMSO and purified by reversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients to give after lyophilisation, the TFA salt of the title compound as a white amorphous solid (97 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C@@:11]2([CH3:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:3]=1[CH2:24][CH2:25]OS(C)(=O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH2:24][CH2:25][N:10]([C@@:11]3([CH3:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12]3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(Cl)c(CCOS(C)(=O)=O)c(N[C@@]2(C)CCN(C(=O)OC(C)(C)C)C2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl(3S)-3-{[6-chloro-2-(methylsulfanyl)-5-{2-[(methylsulfonyl)oxy]ethyl}pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylate (1635 mg, 3.4 mmol) in DMF (34 mL) was added DBU (1.1 mL, 6.8 mmol) and the mixture was stirred at 80° C. for 90 min. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to give the title compound (1.24 g, 95%) as a light yellow-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.80-3.57 (m, 4 H), 3.40-3.35 (m, 1 H), 3.28-3.19 (m, 1 H), 2.91 (t, J=8.9 Hz, 2 H), 2.42 (s, 3 H), 2.39-2.24 (m, 1 H), 2.07-1.94 (m, 1 H), 1.39 (d, J=5.4 Hz, 9 H), 1.28 (s, 3 H). m/z (APCI+) for C17H25ClN4O2S 385.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:23]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:35][CH3:36])(=O)=O.[NH3:37]>CO>[CH:30]1([C:24]2[CH:23]=[C:22]([C:20]3[O:19][N:18]=[C:17]([C:13]4[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH2:7][CH2:6][NH2:37])=[C:11]([CH2:35][CH3:36])[CH:12]=4)[N:21]=3)[CH:27]=[C:26]([O:28][CH3:29])[N:25]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCOS(C)(=O)=O
Reactant: N
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN

Procedure:
A solution of 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propyl methanesulfonate (1.30 g, 2.52 mmol) in 7 N NH3 in methanol (30 mL) is stirred at 55° C. for 24 h. The mixture is concentrated and dried to give crude 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-1-amine (1.24 g) as a pale yellow foam; LC-MS: tR=0.95 min, [M+H]+=437.33.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:13][C:12]2=[O:27])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[NH4+].[Cl-]>[Fe].CCO.O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]2=[O:27])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1N
Yield: 99 %

Procedure:
A solution of 1-(3-methyl-4-nitrophenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.46 g, 1.2 mmol) in 9:1 EtOH/H2O (20 mL) was treated with iron powder (0.62 g, 11.1 mmol) and NH4Cl (33 mg, 0.61 mmol), and the resulting suspension was heated at reflux for 18 h. The reaction mixture was filtered, while hot, through Celite® with portions of CH2Cl2 (2×25 mL) and MeOH (2×25 mL). The filtrates were combined and made basic with 1 N NaOH (10 mL). The solution was extracted with CH2Cl2 (2×40 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated to provide the title compound (0.409 g, 100%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.68 (d, J=7.0 Hz, 1H), 6.96 (s, 1H), 6.92 (dd, J=8.5, 2.0 Hz, 1H), 6.80 (d, J=1.5 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.63 (dd, J=7.0, 2.0 Hz, 1H), 5.11 (s, 2H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][NH:2]C(NC1C=CC=CC=1)=O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN.NC(N)=O.[C:27]([CH2:29][C:30]([OH:32])=O)#[N:28]>C(OC(=O)C)(=O)C>[NH2:28][C:27]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19](=[O:20])[N:2]([CH3:1])[C:30](=[O:32])[CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC(=O)O
Reactant: CNC(=O)Nc1ccccc1
Agent: CN
Agent: NC(N)=O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
N-Methyl-N'-phenylurea was preliminarily prepared from phenyl isocyanate and methylamine by the procedure described in Step 1. Using the urea compound as the starting material, uracil ring was formed by the procedure described in Step 2. N-Methyl-N'-phenylurea (30 g, 0.2M) and cyanoacetic acid (18.8 g, 0.22M) were dissolved in 400 ml of a solvent, acetic anhydride, and heated at 80° C. for 2 hours. The solvent acetic anhydride was distilled off under reduced pressure and 200 ml of water was added to the residue, followed by cooling with ice. A 2N aqueous solution of NaOH (220 ml) was then added and the mixture was stirred for 2 hours. A precipitated solid product was obtained by filtration. The solid product was washed successively with water and methanol and dried to yield 6-amino-3-methyl-1-phenyluracil (yield: 33 g, or 76% based on N-methyl-N'-phenylurea).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (204 mg, 0.60 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (215 mg, 0.64 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.7 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (380 mg, 0.81 mmol) in chloroform (6 mL). DIEA (570 μL, 3.26 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9].OCC(CO)(CO)CO.[CH3:25][C:26]([C@H:28]1[C@@H:32]2[C@@H:33]3[C@@:46]([CH3:49])([CH2:47][CH2:48][C@@:31]2([CH2:55][OH:56])[CH2:30][CH2:29]1)[C@@:45]1([CH3:50])[C@@H:36]([C@:37]2([CH3:54])[C@@H:42]([CH2:43][CH2:44]1)[C:41]([CH3:52])([CH3:51])[C@@H:40]([OH:53])[CH2:39][CH2:38]2)[CH2:35][CH2:34]3)=[CH2:27]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:15])(=[O:14])[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH2:9].[CH3:27][C:26]([C@H:28]1[C@@H:32]2[C@@H:33]3[C@@:46]([CH3:49])([CH2:47][CH2:48][C@@:31]2([CH2:55][OH:56])[CH2:30][CH2:29]1)[C@@:45]1([CH3:50])[C@@H:36]([C@:37]2([CH3:54])[C@@H:42]([CH2:43][CH2:44]1)[C:41]([CH3:52])([CH3:51])[C@@H:40]([OH:53])[CH2:39][CH2:38]2)[CH2:35][CH2:34]3)=[CH2:25]
Reactant: C[C@H](O)C(=O)O
Agent: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(CC(=O)O)C(=O)O
Agent: OCC(CO)(CO)CO
Product: CC(O)C(=O)O
Reaction time: 20 h

Procedure:
Polymerisation was performed as in Example 3, but the amounts of ingredients were following: 85.2 g of L-lactic acid (78 mole-%), 25.9 g of itaconic acid (16.5 mole-%), 1.4 g of pentaerythritol (0.8 mole-%), 25 g of betulin (4.7 mole-%) and 0.0375 g of tin(II)octoate. Total polymerisation time was 20 hours. As product, was obtained hard brittle brownish yellow mass, which was end-functionalised according to the example 11 and finally crosslinked by radicals.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[O:8][CH3:9].[CH2:22]=O.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:22][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: NCCCCO
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Reactant: C=O
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCCO)C1
Yield: 36 %

Procedure:
3-[(3,4-Dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester, paraformaldehyde and 4-amino-butanol were reacted according to the method described for compounds 792–808 to give the tile compound as a yellow oil (0.015 g, 36% yield). 1HNMR (300 MHz, CDCl3) δ: 7.43–7.40 (2H, m), 7.18 (1H, dd, J=8.42,1.83 Hz), 4.81 (2H, s), 4.14 (2H, s), 3.74 (3H, s), 3.63 (2H, t, J=6.40 Hz), 3.51 (2H, t, J=4.01 Hz), 1.68–1.53 (4H, M), 1.43–1.33 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][C:15]=1[F:21].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:15]1[CH:16]=[N+:17]([O-:20])[CH:18]=[CH:19][C:14]=1[C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:7][C:2]=1[C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Nc1cnc(-c2cc[n+]([O-])cc2F)c(Cl)n1)C1CC1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cnc(-c2cc[n+]([O-])cc2F)c(-c2cccnc2)n1)C1CC1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
In a sealed tube three cycles of vacuum and argon were applied to a mixture of the N-[6-chloro-5-(3-fluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (2.23 g, 7.22 mmol), pyridin-3-ylboronic acid (1.15 g, 9.39 mmol) and Cs2CO3 (7.06 g, 21.66 mmol). A solution of 1,4-dioxane:H2O (64 mL, 9:1) was added and argon was bubbled for 5 min, after which, PdCl2dppfCH2Cl2 (0.59 g, 0.72 mmol) was added and argon was again bubbled other 5 min. The reaction mixture was heated at 90° C. for 1 h. Upon the reaction completion the 1,4-dioxane was concentrated in vaccuo, and the obtained residue was adsorbed onto silica gel with 10% MeOH/THF (150 mL) and purified by column chromatography on silica gel eluting with a MeOH/EtOAc gradient (0→20%). The green solid obtained was precipitated with 1% MeOH/CH2Cl2 (5 mL), and washed with 1% MeOH/CH2Cl2 (3×3 mL), CH2Cl2 (3×5 mL), 1% MeOH/Et2O (3×5 mL) and Et2O (4×5 mL) to yield the title compound as a white powder (1.41 g, 56%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:26]=2[CH:27]=1)=[O:22]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=2)=[N:7][C:2]([NH:32][C:29]2[CH:30]=[CH:31][C:25]3[O:24][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:27][C:26]=3[CH:28]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: CC(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-isopropylphenyl)-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to give 5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine. LCMS: retn, time: 26.05 min.; purity: 99%; MS (m/e): 420 (M+), 422 (MH+); 1H NMR (DMSO-d6): δ 10.00 (1H, s), 9.95 (1H, s), 8.31 (1H, d, J=4.8 Hz), 8.11 (1H, s), 7.74 (3H, m), 7.35 (1H, s), 7.35 (1H, t, J=7.2 Hz), 7.12 (1H, d, J=7.2 Hz), 3.99 (3H, s), 2.83 (1H, sept, J=6.9 Hz), 1.20 (6H, d, J=6.9 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(N(CC)CC)C.[N:31]([CH2:34][C:35](OCC)=[O:36])=[C:32]=[O:33]>C1COCC1.C(OCC)(=O)C>[ClH:15].[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:8]2[O:7][CH2:6][CH2:5][NH:4][CH2:3][C@H:2]2[N:1]2[C:35](=[O:36])[CH2:34][NH:31][C:32]2=[O:33])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: CCOC(=O)CN=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: O=C1CNC(=O)N1[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in THF (3 mL) were added triethylamine (0.058 ml) and ethyl isocyanatoacetate (0.047 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, 2.0 M hydrogen chloride-ethanol solution (8 mL) was added to the obtained residue at room temperature, and the mixture was stirred at 80° C. for 3 weeks. The residue obtained by concentration under reduced pressure was washed with diethyl ether to give the title compound (89 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([Br:11])[CH:9]=[CH2:10]>C(OCC)(=O)C>[Br-:11].[CH2:8]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:9]=[CH2:10]
Reactant: CCN(CC)CC
Reactant: C=CCBr
Solvent: CCOC(C)=O
Product: C=CC[N+](CC)(CC)CC
Product: [Br-]
Reaction time: 24 h

Procedure:
20.2 grams of triethyl amine was added to 24.2 grams of allyl bromide in 44 grams of ethyl acetate. A crystalline solid started to separate within 5 minutes. After 24 hours at 25° C., the product was filtered, washed, and dried. The isolated product weighed 41.3 grams and melted at 220°-234° C. with decomposition. Bromide analysis showed 97.5% of the theoretical amount of bromide present in the water-soluble white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([NH2:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[C:28](Cl)(=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)O1>C(Cl)Cl>[NH:51]1[C:52]2[C:48](=[C:47]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([C:11]([NH:14][C:28](=[O:37])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=5)([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:55]=[CH:54][CH:53]=2)[CH:49]=[N:50]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(N)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)NC(C)(C)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (150 mg, 0.5 mmol) in CH2Cl2 (10 mL) was added Et3N (230 μL, 1.6 mmol) and m-anisoyl chloride (160 mg, 0.9 mmol). The resulting mixture stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. A portion (0.2 mmol) of the resulting crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 411 after reverse phase HPLC purification (13 mg). MS (Q1) 529 (M)+