Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[S:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C>O1CCCC1>[CH2:17]([N:4]1[CH2:3][CH2:2][N:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:5]1=[S:6])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCN(CCc1ccccc1)C(=S)NCCCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: S=C1N(CCCc2ccncc2)CCN1CCc1ccccc1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Anhydrous tetrahydrofuran (2.5 ml) was added to a mixture of 1-(2-hydroxyethyl)-1-phenethyl-3-[3-(4-pyridyl)propyl]thiourea (Compound No. 7-2) (601 mg, 1.75 mmol) and triphenylphosphine (913 mg, 3.49 mmol), and the whole was stirred under ice/methanol-cooling. A solution of diisopropyl azodicarboxylate (710 mg, 3.49 mmol) in anhydrous tetrahydrofuran was added dropwise thereto, and after 10 minutes, ethyl acetate (100 ml) was added to the reaction mixture. The whole was washed with a saturated aqueous sodium hydrogencarbonate solution (40 ml) and saturated brine (40 ml) successively, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was filtered off with hexane to give 107 mg (19%) of the titled compound as crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9](O)=[O:10])=[O:6])[CH3:3].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.Cl.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([C:45]([NH2:47])=O)[NH:40]2.OC1C2N=NNC=2C=CC=1>C1COCC1>[C:45]([C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:9](=[O:10])[C@H:8]([C:12]12[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][C:14]([OH:22])([CH2:20]3)[CH2:13]1)[CH2:21]2)[NH:7][C:5]([O:4][C:2]([CH3:23])([CH3:1])[CH3:3])=[O:6])#[N:47]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: -6 °C
Reaction time: 8 h

Procedure:
A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 3) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to −6° C. in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-C1) (13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8° C. The reaction mixture was stirred at 0° C. until all acid was converted to mixed anhydride. (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27]O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 78.9 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (632 mg, 1.2 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.56 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (775 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][N:3]=1.CN([CH:18]=[O:19])C.C(N1C=CN=C1)(N1C=CN=C1)=O>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:14][C:18](=[O:19])[N:8]2[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1N
Reactant: CN(C)C=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
To a microwave vial is added the crude (2-Chloro-5-amino-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 2.329 mmol) and anhydrous DMF (15 ml) followed by 1,1′-carbonyldiimidazole (1.133 g, 6.987 mmol). Sealed vial and microwave heated at 100° C. for 10 min. The reaction mixture is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, 1:1 EtOAC/Hexane) gives the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.O.NN>CCO>[Cl:1][C:2]1[C:3]([CH2:24][NH2:25])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Yield: 64.9 %

Procedure:
To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[CH:12]=[CH:11][S:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[CH:12]=[CH:11][S:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3sccc23)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3sccc23)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a vial containing tert-butyl [(3S)-1-(5-nitrothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (228.4 mg, 0.6035 mmol), iron powder (357.7 mg, 6.405 mmol) and NH4Cl (567.8 mg, 10.61 mmol), EtOH (5.00 mL) was added, followed by water (1.00 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was then filtered through a pad of diatomaceous earth. The diatomaceous earth pad was eluted with a 10% aq. K3PO4 (30 mL), and EtOAc (30 mL). The organic layer was washed with brine (30 mL), then dried over Na2SO4, and concentrated under reduced pressure. The resulting residue (212.9 mg) was used in the next step without further purification. LCMS calc. for C17H25N4O2S (M+H)+: m/z=349.2. found 349.2.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>CN(C)C(=O)C>[Br:25][C:26]1[CH:27]=[C:28]([CH:29]=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH:31]=[CH:32][CH:33]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1cccc(Br)c1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1cccc(Br)c1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.115 g, 0.30 mmol) was reacted with 3-bromobenzaldehyde (0.555 g, 3.0 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 30 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with ethyl acetate (3 mL) and filtered to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.CS(C)=O.[C-:22]#[N:23].[Na+]>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:17])=[CH:4][C:3]=2[CH2:2][C:22]#[N:23])=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: Cc1ccc(Oc2ccc(C)cc2CCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C)cc2CC#N)cc1
Temperature: 36 °C
Reaction time: 4 h

Procedure:
A solution of 108 g. of 3-chloromethyl-4-(4-methyl-phenoxy)-toluene in 70 ml. of dimethylsulfoxide is added dropwise at 20°-25° C. to a suspension of 23 g. of sodium cyanide in 35 ml. of dimethylsulfoxide. The mixture is subsequently stirred for 4 hours at 36° C., then diluted with 1 Liter of water and extracted three times with benzene. The benzene extracts are washed three times with water, then dried over sodium sulfate and evaporated in vacuo, and there is obtained crude 2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile as a brown oil.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[NH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[N:23]=[C:22]([SH:27])[N:21]=1>O.C(=O)(O)[O-].[Na+]>[OH2:3].[OH2:3].[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:22]3[N:23]=[C:24]([NH2:26])[CH:25]=[C:20]([NH2:19])[N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Nc1cc(N)nc(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc(N)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 60 °C
Yield: 82.5 %

Procedure:
2.7 g (0.01 mole) of 7-aminocephalosporanic acid are dissolved in 50 ml of water with the required amount of sodium bicarbonate. 1.7 g (0.013 mole) of 4,6-diamino-2-mercaptopyrimidine and the equivalent amount of sodium bicarbonate are added and the reaction solution is heated to 60° C. for 4 hours, whilst stirring and keeping the pH value constant (pH=7). The mixture is allowed to cool, undissolved material is filtered off and the filtrate is concentrated in vacuo at 30° C. to half its volume. The aqueous solution which remains is extracted several times with ethyl acetate and the aqueous phase is adjusted to a pH of 2 with 2 N hydrochloric acid. The precipitate is filtered off, washed with water until free from chloride and dried in vacuo at 37° C. over potassium hydroxide. 1.61 g of the title compound are obtained. Rf : 0.27 (acetone:glacial acetic acid =10:1) IR (KBr): 1,745 cm-1 (β-lactam band) NMR (d6 -DMSO, 60 MHz):
Reaction SMILES: [CH:1]1([NH:7][CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C>[CH:1]1([N:7]([CH3:8])[CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
In DMF (50 ml) was dissolved N-cyclohexyl-N-methylamine (12.5, 0.11 mol), and to the solution were added potassium carbonate (27.6, 0.20 mol) and 4-nitrobenzylbromide (21.6, 0.10 mol). The mixture was stirred at room temperature for 5 hours. Under reduced pressure, the reaction mixture was concentrated. To the residue was added ethyl acetate, and the mixture was extracted with water. The ethyl acetate layer was washed with saturated sodium chloride solution, dried with MgSO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give N-cyclohexyl-N-methyl-N-(4-nitrobenzyl)amine (24.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:16])[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A stirred solution of benzyl 3-benzyloxyphenyl ketone (3.02 g) in dry tetrahydrofuran (70 mL) at −40° C. is treated with potassium tert-butoxide (1.12 g), portionwise during 10 minutes. The reaction is stirred at −40° C. for 1 hour and is then treated dropwise with a solution of methyl bromoacetate (1.04 g) in tetrahydrofuran (10 mL). The mixture is allowed to stir at ambient temperature for 18 hours. After this time, the reaction is concentrated to dryness and partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulphate and concentrated under reduced pressure. The residue is recrystallised from a mixture of ethyl acetate and pentane, to give methyl (RS)-4-(3-benzyloxyphenyl)-4-oxo-3-phenylbutanoate (1.4 g), m.p. 88-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:18].[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:19][C:3]1[C:2]([Cl:1])=[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]2[C:4]=1[C:5]([NH2:18])=[N:6][CH:7]=[N:8]2
Reactant: Nc1ncnn2c(CN3CCOCC3)c(Cl)cc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CN3CCOCC3)c(Cl)c(Br)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 114.6 %

Procedure:
To a solution of 6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.9 g, 3.36 mmol) in DMF (5 mL) at −20° C. was added 1,3-dibromo-5,5-dimethylhydantoin (0.43 g, 1.51 mmol) portion wise over 30 min. The reaction mixture was stirred for 20 minutes at that temperature. TLC analysis indicated that there was complete conversion of starting material. The reaction was quenched with distilled water (30 mL) as the solution warmed to rt. CH2Cl2 (30 mL) was added to the reaction and the solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with CH2Cl2 (4×20 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated to dryness. The crude material was washed with diethyl ether (10 mL). The white precipitate was collected and dried under vacuum to yield 0.6 g of the above compound (1.73 mmol, yield 51%). 1H-NMR (CD3OD-d4) δ 7.94 (s, 1H), 3.79 (s, 2H), 3.05 (t, J=4.8 Hz, 4H), 2.39 (t, J=4.8 Hz, 4H); MS [M+H]+=347.7; LCMS RT=1.21 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[C@H:28]([OH:33])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1Br>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:11][C:12]1[N:13]=[CH:14][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Sn](C)(C)c1cccnc1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Br)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 71 (0.82 g, 3.4 mmol) in anhydrous toluene (50 ml) were added 0.9 eq (1.10 g) of 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (compound 72, LCMS (method A): Rt: 3.60 min, ([M+H]+=357)) and the resulting mixture was stirred for 2 hours under N2 (room temperature). To this reaction mixture were added 10 mol % of PdCl2(PPH3)2 (240 mg). After the addition, the temperature was raised to 100° C. and the resulting solution was stirred for 18 hours under N2. The reaction mixture was cooled, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to afford 3-[5-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine (73) as an oil (385 mg, 36%). LCMS (method A): Rt: 3.40 min, ([M+H]+=355). 1H-NMR (400 MHz, CDCl3 and HMBC): δ 8.79 (d, J=2 Hz, 1H), 8.66 (dd, J=5 Hz, 2 Hz, 1H), 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7.66 (s, 1H), 7.44-7.40 (m, 1H), 5.17 (s, 2H), 3.56-3.50 (m, 2H), 0.94-0.87 (m, 2H), 0.0 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[OH-].[Na+].C(O)C[OH:31].O>CS(C)=O>[OH:31][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(CO)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 100 °C
Yield: 2 %

Procedure:
To a solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.5 g, 0.0013 mol) in dimethyl sulphoxide (10 ml) was added sodium hydroxide (0.26 g, 0.0065 mol) and ethylene glycol (0.41 g, 0.0065 mol). The reaction mixture was heated at 100° C. for 6 hours, allowed to cool and poured into water (50 ml), then the aqueous mixture extracted with ethyl acetate (3>30 ml). The combined extracts were filtered, dried (Na2SO4) and evaporated under vacuum to provide an oil which was purified by chromatography on silica gel (6g), using a methanol in dichloromethane elution gradient (0-3%) methanol). The solid product was crystallised from hexane-ethyl acetate to afford the title compound as a white solid (2%), m.p. 174°-175° C. Found: C,63.97; H,6.66; N,15.57. C19H24N4O3 requires C,64.03; H,6.79; N,15.72%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:62]=[CH:61][CH:60]=[CH:59][C:43]=1[CH2:44][N:45]1[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]1=[O:58].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:43]2[CH:59]=[CH:60][CH:61]=[CH:62][C:42]=2[O:41][CH3:40])[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2OC)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 75A (0.020 g, 0.062 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.024 g, 59% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 1 H), 1.38 (m, 1 H), 1.54 (m, 2 H), 2.33 (m, 1 H), 2.83 (m, 5 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.83 (m, 4 H), 4.25 (m, 4 H), 4.53 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.93 Hz, 1 H), 6.95 (t, J=6.99 Hz, 1 H), 7.18 (m, 11 H), 7.45 (d, J=9.19 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:17])=[O:5]
Reactant: CNC
Reactant: O=Cc1ccc(F)c(C(=O)O)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc(C=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
The solution of 2-fluoro-5-formylbenzoic acid (3 g, 17.8 mmol) in methylene chloride (10 mL) was added thionyl chloride (2.0 mL, 26.7 mmol) slowly at 0° C. Then the cold reaction mixture was heated to reflux for 3 h. The solution was cooled to 0° C., added dimethylamine (40 wt. % solution in water, 5 mL) slowly, and then stirred at room temperature for 1 h. The solution was washed with water and brine, the organic layer was dried with Na2SO4 and the solvent was removed to get the desired product (2.4 g, yield 76%). LC-MS (ESI) m/z: 196 (M+1)+