Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([NH:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: Cl
Solvent: c1ccccc1
Product: c1ccc(CNC2CCc3cc4c(cc3C2)OCC4)cc1

Procedure:
45 g of the compound of Example 2, 25.4 g of benzaldehyde and 300 ml of benzene are brought to reflux, removing the water formed. The mixture is evaporated to dryness, the residue is taken up with 300 ml of ethanol and 9 g of sodium borohydride are added portionwise, keeping the temperature at approximately 18° C. After one night at room temperature, the ethanol is removed under vacuum and the residue taken up with dilute hydrochloric acid solution. The acid phase is alkalinized and then extracted with ethyl ether. After evaporation of the solvent, the oil obtained is purified on a silica column using a mixture of methylene chloride and methanol (95:5 V/V) as elution solvent.
Reaction SMILES: N.C(O)=O.C(O)(=O)C.[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:24]([NH2:25])[C:23](=[O:26])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[CH3:10]>O.CC(C)=O>[C:9]([O:12][CH2:13][C:14]1[C@H:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:17]2[S:16][CH:15]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: CC(=O)O
Solvent: O
Solvent: O=CO
Product: CC(=O)OCC1=CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O

Procedure:
3-Acetoxymethyl-7β-formamidoceph-2-em-4α-carboxylic acid (1.5 g, 0.5 mmol) was dissolved in dioxan (12 ml) containing 50% conc. hydrochloric acid (1.7 ml.) at room temperature. After 2 hr. the excess solvent was removed by freeze-drying to give solid hydrochloride (1.5 g., 100%). Adjustment of the pH to the isoelectric point with a dilute ammonia solution failed to give a precipitate of the zwitterion. The infrared and n.m.r. results on the freeze-dried solution were consistant with the structure of the compound named in the title. Paper electrophoresis was carried out on Whatman No. 1 paper at pH 1.9 [98% formic acid (16.7 ml), glacial acetic acid (84 ml.), acetone (105 ml) and water (495 ml)] at a potential drop of 125 volts/cm for 20 min. The mobility obtained was 5 cm as compared with 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylic acid which has a mobility of 3.5 cm.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](Cl)=[O:13])=[C:5]2[N:4]=[N:3]1.Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].CN(C=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]([NH:16][CH2:17][C:18](=[O:19])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:13])=[C:5]2[N:4]=[N:3]1
Reactant: NCC(=O)c1ccccc1
Reactant: Cn1nnc2c(C(=O)Cl)ncn2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1nnc2c(C(=O)NCC(=O)c3ccccc3)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl chloride (0.620 g; 2.90 mmol) and 2-aminoacetophenone hydrochloride (0.500 g; 2.90 mmol) was added DMF (6 mL) and pyridine (1.2 mL). The reaction mixture was stirred for 16 hours at room temperature, and then poured onto water. The precipitate was filtered, washed with water, and dried in the vacuum oven, and used without further purification. δH (DMSO-d6) 8.89 (1H, s), 8.68 (1H, t, J=5.6), 8.06 (2H, dd, J=8.3, 1.2), (1H, tt, J=7.4, 1.8), 7.58 (2H, m), 4.86 (1H, d, J=5.6), 3.89 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][CH2:14][C:15]1[N:19]([C:20]2[S:21][C:22]([CH2:34][CH3:35])=[CH:23][C:24]=2[C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:18]([CH3:36])=[N:17][N:16]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([C:24]1[CH:23]=[C:22]([CH2:34][CH3:35])[S:21][C:20]=1[N:19]1[C:18]([CH3:36])=[N:17][N:16]=[C:15]1[CH2:14][NH:13][S:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:11])=[O:10])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNS(=O)(=O)c2ccc(Cl)c(Cl)c2)s1

Procedure:
3,4-Dichlorobenzenesulfonyl chloride and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole are reacted, and treated in the same manner as in Example 48 to give N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzenesulfonamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][O:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:8]1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([N:16]2[CH:15]=[CH:14][S:13][CH:12]2[O:11][CH2:10][CH:9]([OH:7])[CH3:8])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: c1csc(OCC2CO2)n1
Solvent: CCO
Product: CC(O)COC1SC=CN1N1CCOCC1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I of the invention. In this example 1 g. of morpholine is added to a solution of 0.3 g. of 1,2-epoxy-3-(thiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of 1,2-epoxy-3-(thiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-(N-morpholino-3-(thiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:32][O:33][CH2:34][CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:31][C:22]1[C:21]2[N:20]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:18]([CH2:17][CH2:16][CH2:15][NH:14][CH2:1][C:3]3[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=3)[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCNCc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 4.9 %

Procedure:
Methyl 2-(3-formylphenyl)acetate (199 mg) was added to the product of step (iv) (334 mg) in THF (20 mL) at 25° C. under nitrogen. The resulting solution was stirred at rt for 6 h. Sodium triacetoxyborohydride (1183 mg) was added to the reaction mixture at rt under nitrogen and the mixture was stirred at rt for 15 h. The reaction mixture was quenched with water and dissolved in MeOH. The product was purified via RPHPLC, which afforded 25 mg of the desired product as a white solid.
Reaction SMILES: F[C:2]([CH3:9])([CH3:8])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(OCC)(=O)C>[C:15]([NH:4][C:3](=[C:2]([CH3:9])[CH3:8])[C:5]([OH:7])=[O:6])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(F)C(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)=C(NC(=O)c1ccccc1)C(=O)O
Reaction time: 4 h

Procedure:
To a suspension of 3-fluoro-DL-valine (165 mg, 1 mmol) in ethyl acetate (10 mL) was added NaHCO3 (sat. aq., 5 mL) followed by benzoyl chloride (1 mmol). The solution was stirred for 4 h, acidified with 1N HCl, and then extracted into ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated to provide the crude 2-benzamido-3-methylbut-2-enoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[C:5]2[NH:6][C:7](=[O:11])[CH2:8][C:9](=[O:10])[N:4]2[N:3]=1.[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>C(#N)C>[O:28]=[C:27]1[C:26]2[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24](=[O:29])[N:1]1[C:2]1[C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[C:5]2[NH:6][C:7](=[O:11])[CH2:8][C:9](=[O:10])[N:4]2[N:3]=1
Reactant: Nc1nn2c(c1Cc1cccc3ccccc13)NC(=O)CC2=O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: O=C1CC(=O)n2nc(N3C(=O)c4ccccc4C3=O)c(Cc3cccc4ccccc34)c2N1
Temperature: 80 °C
Reaction time: 120 h
Yield: 72.8 %

Procedure:
The solution of 2-amino-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (2.7 g, 8.81 mmol), phthalic anhydride (3.00 g, 20.27 mmol) in Acetonitrile (100 mL) was stirred at 80° C. for 2 days. Additional phthalic anhydride (3.00 g, 20.27 mmol) was added in. The reaction was stirred at 80° C. for 5 days. The reaction was concentrated. To the crude was added DCM (20 mL). The insoluble solid was collected. The filtrate was purified on a silica column (20-60% EtOAc/Hexane) which was combined with the solid from filtration to give the product (2.8 g, 71%). LC/MS: MS (ES+) m/e 437.2 [M+H]+
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([O-])(O)=O.[Na+].O=C1CCC(=O)N1[O:28][C:29](=O)[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(#N)C>O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@H:2]([NH:1][C:29](=[O:28])[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: O=C(CCCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
(Method J15B) A suspension of L-tryptophan (2.040 g, 10 mmol) and NaHCO3 in water (15 ml) was treated with 4-phenyl-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester (15/95) (2.610 g, 10 mmol) followed by the addition of acetonitrile (ca. 15 ml) to get a clear solution. The reaction mixture was stirred at ambient temperature for 12 hours and acetonitrile was removed under reduced pressure. The residue was acidified with citric acid to pH 2 and extracted with ethyl acetate (100 ml). The organic layer was washed with water (2×20 ml), brine (20 ml), and dried (MgSO4). The solvents were evaporated to give the crude product 16/95 (3.160 g, 95%). 1H NMR (DMSO-d6, HMDSO) δ: 1.51-1.82 (2H, m); 1.96-2.24 (2H, m); 2.33-2.64 (2H, m); 2.80-3.38 (2H, m);4.38-4.68 (1H, m); 6.82-7.66 (14H, m); 8.11 (1H, d, J=8.0 Hz); 10.87 (1H, m).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9](O)[CH3:10])[CH:5]=1)([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:21])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Cl:21][CH:9]([C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=1)[CH3:10]
Reactant: CC(C)c1cc(C(C)O)no1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1cc(C(C)Cl)no1
Reaction time: 5 h
Yield: 57.3 %

Procedure:
5.66 g of 1-(5-i-propyl-isoxazol-3-yl)ethanol was dissolved in 30 ml of pyridine, and 7.20 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.63 g of 3-(1-chloroethyl)-5-i-propylisoxazole.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[CH:9][CH:10]=1)=[N+]=[N-].[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[N:26]=[C:27]=S>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH:26][C:27]1[N:6]2[N:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=[CH:10][C:5]2=[CH:4][N:1]=1
Reactant: [N-]=[N+]=NCc1ccc(-c2c(F)cccc2F)nn1
Reactant: S=C=Nc1cnccc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine PMe3 (0.62 mL of 1.0 M solution in THF, 0.62 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 140 mg, 0.57 mmol) in THF (2.5 mL) at RT. The reaction turned purple and an evolution of gas was observed. It was stirred for 15 min at RT. A solution of 4-chloro-3-isothiocyanatopyridine (Preparation XXIV, 106 mg, 0.62 mmol) in THF (1 mL) was added. After 15 min at RT, the reaction was diluted with EtOAc (50 mL) and washed with H2O (10 mL). The aqueous phase was extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine (110 mg, 54% yield) as an orange crystalline solid. MS (ESI, pos. ion) m/z: 350.8 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (s, 1 H), 8.17 (d, J=5.09 Hz, 1 H), 7.79 (d, J=9.59 Hz, 1 H), 7.64 (s, 1 H), 7.40-7.51 (m, 1 H), 7.37 (s, 1 H), 7.32 (d, J=5.09 Hz, 1 H), 7.07 (m, 2 H), 6.57 (dt, J=9.44, 1.64 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 75(a), by reacting g (150 mmol) of 5-bromo-2-hydroxy-benzaldehyde and 17.8 ml (150 mmol) of benzyl bromide in 300 ml of acetone, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 22.8 g (52%) of the expected product are obtained in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:37][S:38]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[Cl:9][C:6]1[CH:5]=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[C:3]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:2]([C:44]2[CH:45]=[CH:46][C:41]([S:38]([CH3:37])(=[O:40])=[O:39])=[CH:42][CH:43]=2)[C:7]=1[CH3:8]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c(OCCN2CCOCC2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(OCCN2CCOCC2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example 125, step D, using N-{1-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine, [4-(methylsulfonyl)phenyl]boronic acid, and sodium carbonate (instead of potassium carbonate) as the starting materials in 27% yield. LCMS for C27H32ClN6O4S (M+H)+: m/z=571.2. Found: 571.3; 1H NMR (400 MHz, DMSO-d6): δ 12.9 (s, 1H), 8.17-8.07 (m, 3H), 8.00 (d, J=7.9 Hz, 2H), 7.67 (s, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 5.80 (s, 1H), 4.15-3.84 (m, 1H), 3.42-3.37 (m, 4H), 3.28 (s, 3H), 2.32-2.25 (m, 2H), 2.17-2.12 (m, 2H), 2.08-2.00 (m, 2H), 1.98 (s, 3H), 1.50 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.CCO.[NH3:28].[NH4+].[Cl-]>C(Cl)(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=2)[O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]([NH2:28])=[NH:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: N#Cc1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N=C(N)c1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reaction time: 72 h

Procedure:
4-[3-(2-Chloro-pyrimidin-4-yloxy)-phenoxymethyl]-benzonitrile (169 mg; 0.5 mmol; Example 6; Stage 6.1) is dissolved in CHCl3 (5 mL) and EtOH (0.5 mL) and cooled to 0° C. At this temperature, HCl gas is gently bubbled through during 20 min. The reaction mixture is kept at 4-5° C. for 72 h. After this time, pentane (10 mL) is added and stirring is continued for 1 h at 0° C. The supernatant is removed by decantation, and the residue (intermediate product) is suspended in MeOH (2 mL). At 0° C., NH3 (0.375 mL 2M solution in MeOH; 0.75 mmol) and NH4Cl (27 mg; 0.5 mmol) are added and the mixture is stirred at rt for 5 h 15 min. More NH3 (0.375 mL 2M solution in MeOH; 0.75 mmol) is added, as well as diethyl ether. After removal of the solvents under reduced pressure, the residue is taken up in EtOAc/water, extracted with water and brine and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to obtain a small amount of the title compound as free base. Since most of the product is in the aqueous layer, the latter is lyophilized and the residue purified twice over reversed phase silica (Lichroprep RP18; 15-25 μm), eluting with H2O/acetonitrile (0->43%) (0.1% TFA in both). After concentration of the solution, the title compound is isolated by lyophilization as TFA salt; ES-MS: [M+H]+; m/z=355; HPLC: AtRet=3.43 min.
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][CH2:11][CH:12]2[CH2:17][NH:16][CH2:15][CH2:14][NH:13]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23]([N:13]1[CH2:14][CH2:15][N:16]([C:23](=[O:24])[C:22]2[CH:21]=[C:20]([O:19][CH3:18])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:17][CH:12]1[CH2:11][O:10][C:8]([N:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])=[O:24]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C(OCC1CNCCN1)N1CCCCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C(COC(=O)N3CCCCC3)C2)cc(OC)c1OC
Yield: 68.5 %

Procedure:
Working again according to a protocol identical to the one used in step 1.3 of Example 1, followed by treating, under the same conditions as those of step 1.4 of Example 1, 0.5 g of 2-(1′-piperidinocarbonyloxymethyl)piperazine hydrochloride with 1.1 g of 3,4,5-trimethoxybenzoyl chloride, 0.8 g of 1,4-bis(3′,4′,5′-trimethoxybenzoyl)-2-(1′-piperidinocarbonyloxymethyl)piperazine is obtained. Yield: 56%. Melting point: 146.7° C.
Reaction SMILES: [OH:1][C:2]([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C@H:25]([O:38][Si](C(C)(C)C)(C)C)[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30](=[O:37])[NH:31]3)[CH3:13])[CH2:8][CH2:7]1)=[O:4].F.F.F.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[OH:1][C:2]([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C@H:25]([OH:38])[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30](=[O:37])[NH:31]3)[CH3:13])[CH2:8][CH2:7]1)=[O:4]
Reactant: CN(CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CCCCCCCCCNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-4-[(9-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}nonyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 7; 0.8 g, 0.13 mmol) in tetrahydrofuran (5.1 mL) was added triethylamine trihydrofluoride (0.14 mL, 0.89 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 hours. The crude reaction was diluted with methylene chloride and the organic layer washed with sodium bicarbonate and brine, dried, filtered and evaporated. The crude product was purified by preparative reversed-phase HPLC (System 1) obtaining the title compound as a colourless solid (61%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)N(C)C)c2n(c1=O)CCS2
Yield: 317.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with dimethyl aminosulfonyl chloride (76 mg, 0.528 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 0.08 g of the product (32% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(F)c2)C1
Solvent: C1CCOC1
Product: Fc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 111.4 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-fluorophenyl)piperidin-1-yl]methanone (1.21 g, 3.51 mmol) was treated with BH3 THF according to the above general procedure. 1.28 g crude product was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([S:24]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
To a stirred ice-cooled solution of 4-(dimethylamino)piperidine (1.2 mL, 9.4 mmol), triethylamine (2.6 mL, 19 mmol), and 4-dimethylaminopyridine (0.012 g, 0.094 mmol) in DCM (18 mL) was added 6-chloropyridine-3-sulfonyl chloride (2.0 g, 9.4 mmol) in one portion. The resulting mixture was stirred at 0° C. for 1.5 h. Upon workup, the mixture was directly subjected to combi-flash column chromatography (methanol/DCM) to give compound 363 (2.7 g, 94% yield) as a white solid. LCMS-ESI (POS), M/Z, M+1: Found 304.0.