Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:41])[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:9]1([N:32]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C:33](=[O:41])[OH:34])[CH:10]=[CH:11][CH:23]=[CH:24][CH:25]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[CH:27]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Product: O=C(O)N(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (800 mg, 2.16 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (508 mg, 2.37 mmol) and diisopropylethylamine (0.75 mL, 4.52 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with 5% NaOH (aq), dried over anhydrous sodium sulfate, filtered and concentrated. Treatment of the residue with hot isopropyl ether and purified from isopropyl ether/methanol provided the title compound as a white solid (574 mg). MS (APCI 10V) AP+ 455.3, 376.2, 335.2, AP− 453.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.46 (td, J=5.86, 0.97 Hz, 2H) 2.58 (td, J=5.82, 1.16 Hz, 2H) 3.51-3.60 (m, 2H) 3.61-3.70 (m, 2H) 6.46 (s, 1H) 6.98-7.07 (m, 2H) 7.09-7.19 (m, 2H) 7.34 (ddd, J=8.41, 4.81, 0.65 Hz, 1H) 7.40 (td, J=7.69, 0.74 Hz, 1H) 7.91 (ddd, J=8.38, 2.58, 1.44 Hz, 1H) 8.08 (ddd, J=8.73, 2.61, 0.55 Hz, 1H) 8.16 (dd, J=4.84, 1.06 Hz, 1H) 8.43 (td, J=1.74, 0.91 Hz, 1H) 8.58 (d, J=1.88 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C=O)c(O)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cc(CO)c(O)cc1O
Reaction time: 1 h
Yield: 65.3 %

Procedure:
One gram of 5-acetyl-2,4-dihydroxybenzaldehyde was hydrogenated in the presence of 1 g of 10% palladium on carbon in 150 ml of ethanol. After about 1 hour, hydrogen uptake ceased and hydrogenation was terminated. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in approximately 30 ml of ethyl acetate and cooled in the refrigerator. The resulting solid was recovered by filtration affording 0.66 g of the desired title intermediate, m.p. =151°-152° C. The same reaction when run on a 5-fold scale provide 2.76 g of material.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2O)[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][CH:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])(=O)=O.[OH2:54]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:54])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44]
Reactant: CNCCCCCC1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Reactant: O
Solvent: CN(C)C=O
Product: CN(CCCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 1.77 g of 11β-fluoro-7x-[5-(methylamino)-pentyl]oestra-1,3,5(10)-triene-3,17β-diol in 18 ml of dimethylformamide is stirred at a bath temperature of 80° C. for 1 hour with 1.4 g of 8,8,9,9,9-penta-fluorononyl tosylate. The mixture is then added to water, extracted 3 times with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulphate, concentrated in vacuo and the residue is chromatographed on silica gel using dichloromethane/methanol. 11β-Fluoro-7α-{5-[methyl(8,8,9,9,9-penta-fluorononyl)amino]pentyl}oestra-1,3,5(10)-triene-3,17β-diol is obtained as crystals of melting point 11° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[C:15]#[N:16].[CH2:17](O)[CH2:18][OH:19].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:15]([CH:10]1[CH2:11][CH2:12][C:13]2([O:19][CH2:18][CH2:17][O:14]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])#[N:16]
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: N#CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (20 g.), ethylene glycol (5.6 g.), p-toluenesulphonic acid (1 g.) and benzene 160 ml.) was heated to reflux for 210 minutes with continuous removal of water. The mixture was cooled to ambient temperature, anhydrous sodium carbonate was added and, after filtration through a bed of sodium carbonate, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (19.3 g.), b.p. 166° C-182° C./0.1 mm.Hg. This material was used as a starting material in the next stage, as aliquot being redistilled to b.p. 177°-179° C./0.1 mm.Hg for elemental analysis:
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[N:40]=[CH:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[CH:55]=[C:54]2[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])[CH2:53]2)=[CH:48][CH:47]=1)=[O:45]>C(#N)C>[CH2:27]([O:34][C:35]1[N:40]=[CH:39][N:38]([CH2:43][C:44](=[O:45])[C:46]2[CH:55]=[C:54]3[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:58])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Reactant: O=c1cc(OCc2ccccc2)nc[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Solvent: CC#N
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2

Procedure:
6-Benzyloxy-3-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-3H-pyrimidin-4-one is prepared following preparation 15b from 850 mg (4.20 mmol) 6-benzyloxy-3H-pyrimidin-4-one and 1.35 g (4.41 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone in acetonitrile as solvent (purification via reversed HPLC chromatography).
Reaction SMILES: [CH:1]1([N:8]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:9](=[O:24])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=2[OH:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([O:41][C:42]([NH:44][CH2:45][C:46](O)=[O:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][C:42]([NH:44][CH2:45][C:46]([O:23][C:12]1[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:9]([N:8]([CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[O:24])=[O:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(O)c(C(C)(C)C)c1
Product: COc1cc(NC(=O)N(c2ccc(N(C)C)cc2)C2CCCCCC2)c(OC(=O)CNC(=O)OCc2ccccc2)c(C(C)(C)C)c1

Procedure:
2-[3-Cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol and N-benzyloxycarbonylglycine were treated in the same manner as described in Example 172 (1) to give O-(N-benzyloxycarbonylglycyl)-2-[3-cycloheptyl-3-(4-dimethylaminophenyl)ureido]-4-methoxy-6-tert-butylphenol.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][C@H:12]1[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O.[C:46]1([CH3:55])[CH:51]=[CH:50][C:49]([S:52]([O-:54])=[O:53])=[CH:48][CH:47]=1.[Na+]>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:46]1([CH3:55])[CH:51]=[CH:50][C:49]([S:52]([S:11][C@H:12]2[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:14](=[O:33])[C@H:13]2[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-nitrobenzyl 2-[(3R,4R)-4-[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIc, 3.25 g, 0.005 mole) in acetone (90 mL) and water (10 mL) was treated at room temperature with silver nitrate (1.06 g, 0.00625 mole), followed by treatment with a solution of sodium p-toluenesulfinate hydrate (0.90 g, 0.050 mole) in acetone (70 mL) - water (10 mL). The slurry was stirred for 1 h at room temperature under darkness. It was then filtered through Celite, which was washed with acetone. The volume of the filterate was reduced in vacuo, and the product was extracted into ether (3×250 mL). The ether phase was dried over magnesium sulfate and concentrated. Flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the pure title product, XIIId, as a solid (2.053 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[NH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>C(#N)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:14]1[C:15](=[O:17])[N:30]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Br:1])=[CH:3][C:4]=2[CH2:13]1
Reactant: NCC1CC1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CCl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
(S)-dimethyl 2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (630 mg, 1.6 mmol) was dissolved in acetonitrile (5 mL). Potassium carbonate (560 mg, 4.1 mmol) was added to the mixture followed by (aminomethyl)cyclopropane (700 μL, 8.1 mmol). Mixture was heated to reflux and held with stirring for 1.5 hours. Mixture was cooled to room temperature. Mixture was filtered. Filtrate was concentrated by roto-vap. Residue was dissolved in a mixture of toluene (10 mL) and acetic acid (1 mL). Mixture was heated to reflux and held with stirring for 18 hours. Mixture was concentrated by roto-vap. Silica gel chromatography (ethyl acetate-hexanes) afforded the title compound as tan solid in 64% yield. MS m/e (M+H)+=406.0, 408.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[I:21]Cl.C([O-])(=O)C.[Na+].COC(=O)NC1SC2C=CC=C(OC)C=2N=1>C(O)(=O)C>[I:21][C:6]1[C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: COC(=O)Nc1nc2c(OC)cccc2s1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 93 %

Procedure:
Iodination of 5-methyl-thiophene-2-carboxylic acid (4-methoxy-benzothiazol-2-yl)-amide (5.17 g, 17 mmol) with iodine monochloride (2.26 ml, 44 mmol), sodium acetate (3.63 g, 44 mmol) and acetic acid (200 ml) in the same manner as described for (4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester affords the product as off-white solid in 93% yield. MS: m/e=430 (M+).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)[CH:54]=[N:55][CH:56]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)[CH:54]=[N:55][CH:56]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1cncc(-c2cccc(N)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(5-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 56% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:19][C:17]([CH3:20])([S:21]([NH:23][CH:24]([C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11])[CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])[CH3:18]
Reactant: CCOc1cccc(F)c1Br
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OCC
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of 2-bromo-1-ethoxy-3-fluorobenzene (3.520 g; 16.10 mmol) in anh. THF (60 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (10.05 ml; 16.10 mmol). The resulting solution was further stirred at −78° C. for 5 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (2.650 g; 10.70 mmol) in anh. THF (20 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (75 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate as a yellow oil. LC-MS (conditions A): tR=0.85 min. and [M+H]+: 388.35 g/mol; tR=0.88 min. and [M+H]+: 388.37 g/mol (mixture of diastereoisomers).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15]CC)=O)[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:15])[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Aqueous NaOH (1.11 g, 27.88 mmol) was added to a solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (5 g, 18.58 mmol) in EtOH (50 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Solid obtained was filtered and dried under reduced pressure to obtain corresponding acid. The crude acid (4.4 g, 18.2 mmol) was then dissolved in DMSO (20 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (5.55 g, 36.51 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYB OP (14.24 g, 27.38 mmol) was added to it and stifling was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain a solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (4 g, 58.5%).
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][CH2:23]Cl.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][O:22][CH3:23])[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCCl
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCN1C(=O)N([C@H](C)c2ccccc2)[C@H]2COC(=O)[C@H]21
Temperature: 5 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
4.0 g (93 mmol) sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 19 g (77 mmol) of (3aS,6aR)-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H,3aH)-dione and 9.42 g (120 mmol) of chloromethyl methyl ether in 200 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 2 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 50 ml of water and 100 ml of dichloromethane, the phases were separated and the aqueous phase was extracted 2 times with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After chromatographing the oily residue over silica gel with 500 ml of dichloromethane/ethyl acetate and concentration of the fractions, 4.0 g (18 percent) of the title product was obtained as white powder. Concerning the product:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[CH3:15][C@@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:22][CH:20]1[CH2:19][N:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5](=[O:14])[NH:4][CH:3]=2)[CH2:17][CH:16]([CH3:15])[O:21]1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)[nH]cc(N3CC(C)OC(C)C3)c2c1
Yield: 48.5 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.2 g, 0.787 mmol) and (2S,6R)-2,6-dimethylmorpholine (0.181 g, 1.574 mmol) in ethylene glycol (2.5 ml) was added DIPEA (0.412 ml, 2.361 mmol). The reaction was irradiated in microwave at 145° C. for 1.5 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.11 g, 48.5%) as solid. MS: MS m/z 289.18 (M++1).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH3:13])[CH:6]=1.C1([Li])C=CC=CC=1.CN(C)[CH:23]=[O:24].S(=O)(=O)(O)O>CCOCC>[Cl:11][C:8]1[C:7]([O:12][CH3:13])=[C:6]([C:5]([OH:4])=[CH:10][CH:9]=1)[CH:23]=[O:24]
Reactant: COCOc1ccc(Cl)c(OC)c1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COc1c(Cl)ccc(O)c1C=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chloro-3-methoxyphenol methoxymethyl ether (3.1 g, 0.0153 M) in dry ether (3.5 ml) was added dropwise to a solution of phenyllithium (from 0.21 g lithium and 2.4 g bromobanzene) in dry ether (12 ml) under nitrogen and the mixture stirred at room temperature (3 days). A solution of dry dimethylformamide (1.12 g, 0.0153 M) in dry ether (1 ml) was then added dropwise over 15 mins and the mixture stirred at room temperature (1 hr). The reaction mixture was poured into 2 N sulphuric acid (100 ml) and extracted with ethyl acetate. The combined extracts were dried (sodium sulphate) and evaporated. The residue was dissolved in methanol (25 ml), 3 N hydrochloric acid (10 ml) added and the resultant solution stirred at 65° C. for 30 mins. The solvent was removed in vacuo and the residue diluted with water (50 ml) and extracted with ether. The combined extracts were dried (sodium sulphate) and evaporated. The residue was chromatographed on silica (MFC) eluting with chloroform. The fractions were combined and evaporated to give 3-chloro-6-hydroxy-2-methoxybenzaldehyde as an oil which crystallised on standing. (Found: m/e 186.0084. C8H7ClO3 requires M185.0082).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9](CC2C=CC=CC=2)[CH:10]=[C:11]([O:15]CC2C=CC=CC=2)[C:12](=[O:14])[CH:13]=1.O.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1.[H][H]>CN(C)C=O.[Pd]>[C:31]1([CH3:41])[CH:32]=[CH:33][C:34]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:35][CH:36]=1.[OH:15][C:11]1[C:12](=[O:14])[CH:13]=[C:8]([CH2:7][N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[NH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=C1NCCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCN1Cc1cc(=O)c(O)c[nH]1
Yield: 84.4 %

Procedure:
To a solution of 2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)pyridinone (4.98 g; 12.8 mmol) in dimethylformamide (90 ml) was added p-toluenesulfonic acid monohydrate (4.86 g; 25.6 mmol) and palladium on charcoal (1.0 g), and hydrogen was bubbled through the mixture for 30 minutes. The catalyst was filtered off by suction and the filtrate evaporated in vacuo. The residue was triturated with dichloromethane and ether, and the product filtered off by suction, yielding 4.12 g of the title compound, melting point 195° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: O=C(CCl)N1CCOCC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)N4CCOCC4)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 5 of Example 4 from 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 4, Step 4) and 4-(chloroacetyl)morpholine (B. G. Hazra; V. S. Pore; S. P. Maybhate, Org. Prep. Proced. Int., 1989, 21, 355-8).