Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[C:14]([C:5]2=[N:4][N:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[C:15]1([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]3=[N:4][N:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:6]3[N:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nnc2c3ccccc3c(-c3ccccc3)nn12
Reactant: C1CCNC1
Solvent: CCO
Product: c1ccc(-c2nn3c(N4CCCC4)nnc3c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 3-chloro-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine (4.5 g), pyrrolidine (6 ml) and ethanol (40 ml) is poured in a steel cylinder and heated to 100° C. for 8 hours. Then the mixture is cooled, and concentrated to dryness by evaporating off the solvent. The obtained residue is washed with water and crystallized from ethanol giving 3.5 g of the compound of the title. M.p. 245°-47° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:8]2([OH:11])[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[CH2:14][CH2:13]1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: OC1(C2CC2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 4 h

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (2 g, 12.80 mmol) was dissolved in dry tetrahydrofuran (20 mL). The reaction mixture was cooled to −78° C. Cyclopropylmagnesium bromide (51.2 mL, 25.61 mmol) was added dropwise over a period of 10 min. The reaction mixture was stirred for 4 h, quenched with sat. NH4Cl and extracted with ethyl acetate. The solvent was evaporated and the crude product was used without further purification in the next step.
Reaction SMILES: [Br:1]Br.[F:3][CH:4]1[CH2:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]1=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:1][C:4]1([F:3])[CH2:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]1=[O:13]
Reactant: BrBr
Reactant: O=C1c2ccsc2CCC1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccsc2CCC1(F)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Add a solution of bromine (10.08 g, 63.1 mmol, 1.1 equiv.) in dry carbon tetrachloride (60 mL) dropwise via addition funnel over 1 h20 min to a cold (0° C.) solution of 5-fluoro-6,7-dihydro-5H-benzo[b]thiophen-4-one (9.72 g, 57.1 mmol, 1 equiv.) in dry diethyl ether (300 mL). Once all the bromine is added warm to room temperature for 2 hours and add more bromine (0.7 M in CCl4, 7 mL, 4.9 mmol, 0.09 equiv.) and stir the reaction mixture at room temperature for 1 hr before adding saturated aqueous sodium thiosulfate. The layers are separated and the aqueous layer is extracted with diethyl ether (three times). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purify the resultant crude material by medium pressure liquid chromatography eluting with 0 to 20% ethyl acetate in hexanes to afford the title compound (6.976 g, 49%). δH (400 MHz, CDCl3) 2.67-2.78 (m, 1H), 2.93 (dddd, 1H, J=14, 4, 4, 4 Hz), 3.24-3.31 (m, 2H), 7.21 (d, 1H, J=6 Hz), 7.45 (d, 1H, J=6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(O[CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: COC(=O)c1cccc(O)c1
Product: COC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1

Procedure:
Coupling of methyl 3-hydroxybenzoate with 2-(tert-butoxycarbonylamino)ethyl methanesulfonate following the method used in Example 9 gave methyl 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoate as a light yellow oil. Yield (0.65 g, 84%): 1H NMR (400 MHz, CD3OD) δ 7.36 (t, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.16 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 6.99 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 4.03 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][CH2:31][O:32][C:25]=4[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[ I]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-ethylendioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:12]([I:47])=[C:13]([C:33]([NH:35][CH2:36][CH:37]([O:43]C(=O)C)[CH2:38][O:39]C(=O)C)=[O:34])[C:14]([I:32])=[C:15]([C:18]([NH:20][CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][O:24]C(=O)C)=[O:19])[C:16]=2[I:17])[C:6]1=[O:48])(=O)C.C[O-].[Na+].[Na]>CO>[OH:43][CH:37]([CH2:38][OH:39])[CH2:36][NH:35][C:33]([C:13]1[C:12]([I:47])=[C:11]([N:7]2[CH2:8][CH2:9][CH2:10][CH:5]([OH:4])[C:6]2=[O:48])[C:16]([I:17])=[C:15]([C:18]([NH:20][CH2:21][CH:22]([OH:28])[CH2:23][OH:24])=[O:19])[C:14]=1[I:32])=[O:34]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(OC(C)=O)C2=O)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2CCCC(O)C2=O)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 5-[3-(acetyloxy)-2-oxo-1-piperidinyl]-N,N'-bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 8c (4 g, 4.3 mmol) In methanol (20 ml) was treated with a solution of sodium methoxide in methanol, prepared from sodium (30 mg, 1.3 mmol) and anhydrous methanol (20 ml), and the mixture was stirred at room temperature for 2 hours. The pH of the solution was adjusted down to 7 by the addition of Dowex-50 (H+) resin. The mixture was filtered and the filtrate was freed of the solvent to obtain the crude product. Purification by low pressure reverse phase column chromatography over the CHP-2OP resin furnished analytically pure N,N'-Bis[2,3-dihydroxypropyl]-5-(3-hydroxy-2-oxo-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide as a snow-white glassy solid (2.3 g, 78% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:10]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1c(O)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2c(F)cccc2OC1C(F)(F)F
Yield: 62.2 %

Procedure:
A mixture of 8.7 g (62 mmole) of 2-fluoro-6-hydroxybenzaldehyde, 18.6 mL (20.9 g, 124 mmole) of ethyl trifluorocrotonate and 17.3 mL (12.6 g, 124 mmole) of triethylamine was heated to reflux. After 3 hrs an additional 18.6 mL of ethyl trifluorocrotonate and 2 g of potassium carbonate was added and the mixture heated for 3 days. The mixture was allowed to cool, concd in vacuo, diluted with 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with 1N HCl, brine, dried and concd to afford a dark oil. Kugelrohr distillation (0.2 torr, 50° C.) afforded 11.2 g (62%) of a white solid: mp 45.5-47.0° C.; 1H NMR (CDCl3/400 MHz) 1.33 (t, 3H, J=7.1 Hz), 4.30 (m, 2H), 5.68 (q, 1H, J=6.8 Hz), 6.70 (t, 1H, J=9.0 Hz), 6.76 (d, 1H, J=8.3 Hz), 7.24 (q, 1H, J=7.2 Hz), 7.92 (s, 1H); 19F NMR (CDCl3/ 400 MHz) −78.9 (d, 3F, J=7.7 Hz), −118.9 (m, 1F); 13C NMR (CDCl3/100 MHz) 14.2, 61.6, 70.7 (q, J=33.2 Hz), 108.7 (d, J=18.7 Hz), 109.2 (d, CH, J=20.6 Hz), 111.9 (d, CH, J=3.2 Hz), 117.0, 123.3 (q, J=287.5 Hz), 129.9 (d, CH, J=5.0 Hz), 133.2 (d, CH, J=10.3 Hz), 153.9, 158.5, 162.3 (d, J=253.5 Hz); MS(ES+) 291 (M+1, 100); MS(EI) 290 (M+, 13), 245 (18), 221 (100), 193 (99); HRMS (EI) m/z calcd for (C13H10O3F4) 290.0566, found 290.0589.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Br:13]N1C(=O)CCC1=O.O>C(#N)C.[Fe](Cl)(Cl)Cl>[Br:13][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:10])[F:11])[C:2]([NH2:1])=[C:7]([F:8])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(F)cccc1C(F)(F)F
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Solvent: O
Product: Nc1c(F)cc(Br)cc1C(F)(F)F
Yield: 96.9 %

Procedure:
To a solution of 2-amino-3-fluorobenzotrifluoride (0.7 ml, 5.6 mmol) in acetonitrile (2 ml) was added N-bromosuccinimide (994 mg, 5.6 mmol), followed by iron (III) chloride (90.1 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 90 min, before addition of water (20 ml). The mixture was extracted with tert-butyl methyl ether (2×15 ml) and the combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (1.4 g), which was used directly.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:16]([N:18]1[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:1][C:19]1=[O:20])[CH3:17]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1c(=O)[nH]c2cc(C(=O)OC)ccc2c1=O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-aminoterephthalate (4.18 g), ethyl isocyanate (2.58 ml) and triethylamine (1.0 ml) in toluene (20 ml) was heated at 70° C. for 15 hr. After concentration, methanol (50 ml) and concentrated hydrochloric acid (10 ml) was added and the mixture was stirred at room temperature for 5 hr. After concentration, the residue was washed with water (50 ml) and methanol (50 ml) and dried to give the object compound (2.23 g).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[P:13]([O-:20])([O-:19])([O:15]C(=O)C)=O.[Cl-].[Ca+2:22].[Cl-]>CC(C)=O>[P:13]([O:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][O:12][P:13]([O-:20])([O-:19])=[O:15])[OH:10])[OH:8])[OH:6])=[O:4])([O-:20])([O-:19])=[O:15].[Ca+2:22].[Ca+2:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(=O)OP(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: O=C(COP(=O)([O-])[O-])[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Propionibacterium freudenreichii IFO12425 was inoculated into 10 liters of a culture medium (pH: 6.5) containing 0.35% of glucose, 0.30% of peptone, 0.30% of yeast extract, and 0.05% of KH2PO4. This bacteria was cultured at 30° C. using a jar fermenter; 20 g of wet microorganisms were collected by centrifugation and immersed in acetone for 2 hours. Separately, 30 liters of tris-HCl solution prepared in the same manner as in Example 1 was placed in a 70-liter reaction vessel. To the tris-HCl solution was added 20 g of the acetone-treated microorganism body. The resulting solution was maintained at 30° C., and 20 liters of acetyl phosphate prepared as in the Reference Example was added in 5-liter portions. The reaction solution yielded 3.6 kg of dicalcium fructose-1,6-diphosphate salt following treatment with calcium chloride in the same manner as described in Example 1.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.B1([O-])O[O:17]1.O.O.O.O.[Na+]>C1COCC1>[OH:17][CH:3]1[CH2:4][CH2:5][CH:1]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2]1
Reactant: [O-]B1OO1
Reactant: O=C(OCc1ccccc1)C1CC=CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The benzyl cyclopent-3-ene-1-carboxylate (2.0 g, 9.89 mmol) was dissolved in 20 mL of THF and cooled to 0° C. under nitrogen. Borane-THF complex (0.95 mL, 9.89 mmol) was added via syringe and the mixture was stirred for 30 minutes at 0° C. Sodium perborate tetrahydrate solution (100 mL of 0.33 M aqueous solution) was added, and after 30 minutes the reaction mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine and then dried over sodium sulfate. Filtration and concentration provided the crude product which was purified by chromatography on silica gel eluting with 10 to 30% EtOAc in hexanes to provide benzyl 3-hydroxycyclopentanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH:16]1([CH2:19][NH:20][C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[O:37])=[CH:23][CH:24]=3)[C:13]([CH3:14])=[C:12]([F:15])[CH:11]=2)=[O:6])[CH2:10][CH2:9]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1Br
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 80 °C
Yield: 61.9 %

Procedure:
3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (Intermediate 1, 40 mg, 0.15 mmol), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (45 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol) were dissolved in DME (3 ml) and aqueous sodium carbonate (1M, 150 μl) was added. The mixture was refluxed at 80° C. for 16 hours. Solvent was removed in vacuo and the residue was purified by silica biotage chromatography, eluting with ethyl acetate:cyclohexane (2:) then 100% ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-5-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide (34 mg, 62%)
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH2:22])=[O:21]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH:22][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:21]
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1cccc(Cl)c1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: N#CCC(=O)NC(=O)NCc1cccc(Cl)c1
Reaction time: 4 h
Yield: 84.8 %

Procedure:
3.76 g of 98% cyanoacetic acid and 14 ml of acetic anhydride were heated for 1 hour at 65° C. A solution of 7.73 g of (3-chlorobenzyl)urea in 55 ml THF was added and the mixture kept for 4 hours at 65° C. The THF was removed in vacuo and the residue diluted with 50 ml of toluene. The solid was collected and washed to give the title compound (8.94 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[C:18]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:53])[C@@H:33]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[CH2:34][N:35]([CH:43]([CH3:45])[CH3:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:28][CH2:27]2)=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:52][C:49]1[CH:48]=[CH:47][C:46]([C@H:33]([C:32](=[O:53])[N:29]2[CH2:30][CH2:31][N:26]([C:18]3[C:17]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:22][N:21]=[C:20]4[NH:23][CH:24]=[CH:25][C:19]=34)[CH2:27][CH2:28]2)[CH2:34][N:35]([CH:43]([CH3:45])[CH3:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:51][CH:50]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccnc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 63.9 %

Procedure:
Pyridin-3-ylboronic acid (20 mg, 0.17 mmol), PS-tetrakis (41 mg, 0.0041 mmol) and sodium carbonate (18 mg, 0.17 mmol, 2N aqueous solution) were added to (S)-tert-butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (50 mg, 0.083 mmol, see Example 4) in degassed (Ar) dioxane (1 mL). The reaction was heated to 160° C. for 1 hour under microwave irradiation. After cooling down, the reaction was diluted with DCM, filtered, dried over MgSO4 and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (water:ACN 4:1 to 1:9) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (32 mg, 64% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10].CNC>CO>[C:19]([C:15]1[CH:16]=[C:17]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(C)(C=O)CO
Agent: CNC
Solvent: CO
Solvent: O
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 92 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 185 g (0.9 mol) of 2,6-di-t-butylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. and under the autogenous pressure of 20-30 bar for 10 h. Workup of the reaction mixture by distillation yields 238 g (92%) of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 126°-127° C.; melting point 75°-77° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=O)[CH3:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[CH3:26][O:27][NH2:28].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[N:28][O:27][CH3:26])[CH3:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: CON
Reactant: COC(=O)c1c(Sc2nc(OC)cc(OC)n2)cccc1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CON=C(C)c1cccc(Sc2nc(OC)cc(OC)n2)c1C(=O)OC
Temperature: 25 °C
Yield: 60 %

Procedure:
1.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)thio]-6-acetylbenzoate and 0.5 g of methoxyamine hydrochloride were dissolved in 6 ml of methanol, and the resultant solution was refluxed for 15 minutes. After cooling the mixed liquor to room temperature, 0.8 g of potassium carbonate was added to this liquor and the resultant liquor was heat-refluxed for 3 hours. The reaction liquor was poured into a large amount of water, and an oily product thus precipitated was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and was dried to distill off ethyl acetate under reduced pressure. The residue thus obtained was purified by chromatography to obtain 0.65 g of the aimed compound (refractive index=1.5709) at a yield of 59%.
Reaction SMILES: C(OC(N1C[CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1CCNC[C:41]1(C)C)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH2:13][N:12]([CH2:16][C:17]2[S:18][C:19]3[C:24]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:23][C:22]([Cl:31])=[N:21][C:20]=3[N:32]=2)[CH2:11][C:10]1([CH3:14])[CH3:9])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1(C)C

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4, 5-d]-pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (100 mg, 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][CH:12]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2].F[B-](F)(F)F.[CH3:25][O+](C)C>C(Cl)Cl>[CH3:25][O:19][C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:18]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(C=Cc2ccccc2[N+](=O)[O-])N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C=Cc2ccccc2[N+](=O)[O-])CCCC1

Procedure:
The product of Example 155 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][C:17](=[O:20])[NH:18][NH2:19])([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([NH:18][N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:20])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of phthalic anhydride (29.63 g, 200 mmol) and tert-butylcarbazate (26.40 g, 200 mmole) in toluene was refluxed for two hours using a Dean-Stark trap. The mixture was allowed to cool and crystallize overnight. The crystals were filtered of and washed with cold toluene. The crystals were dried in vacuum.