Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O.Cl.[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][N:15]([CH3:14])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1ccc(O)c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc(N(C)C)ccc1O
Temperature: 0 °C
Yield: 34 %

Procedure:
0.5 g (3 mmol) of 5-(dimethylamino)-2-hydroxybenzaldehyde (Bull. Chem. Soc. Jpn. (1978), 51 (8), 2433–2434) and 0.72 g (3.33 mmol) of N-methyl2-(4-nitrophenyl)ethylamine hydrochloride are placed in solution in 30 ml of anhydrous methanol under an inert atmosphere in the presence of 0.65 ml of triethylamine (4.5 mmol). The reaction mixture is stirred vigorously for 18 hours before the addition, by portions, of 126 mg (3.33 mmol) of NaBH4. Stirring is maintained for a further 4 hours before adding 10 ml of ice-cold water. The reaction mixture is extracted twice with 50 ml of CH2Cl2. The organic phase is washed with 10 ml of water, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: CH2Cl2/MeOH: 97/3). The expected product is obtained in the form of a brown oil with a yield of 34% (0.34 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H][H].C>CO.C(O)(=O)C.[Pd]>[OH:11][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[C:9]=1[CH3:10]
Reactant: [H][H]
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(O)c(C)c1O
Yield: 30.5 %

Procedure:
1 g (6.5 mmol) of 2,4-dihydroxy-3-methylbenzaldehyde is hydrogenated, at 3 bar hydrogen pressure for 24 h, with 100 mg of Pd on active charcoal (10%) in 100 ml of methanol and 1 ml of glacial acetic acid. A further 100 mg of Pd on active charcoal (20%) are added and the mixture is hydrogenated at 3 bar hydrogen pressure for 12 h. The catalyst is filtered off, the solvent is removed in vacuo and the residue is purified by chromatography (dichloromethane/acetone). 274 mg (30%) of 1,3-dihydroxy-2,4-dimethylbenzene are obtained.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=O)[CH2:3][CH2:2]1.[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][NH2:23]>CO.C(O)(=O)C>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22]/[N:23]=[C:4](/[CH:1]1[CH2:3][CH2:2]1)\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C(c1ccccn1)C1CC1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(N/N=C(\c2ccccn2)C2CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of cyclopropyl-(2-pyridyl)-methanone (1,00 g, 7,40 mmol) and 1-methyl-2-hydrazinobenzimidazole (1.20 g, 7.40 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after the addition of 6 drops of glacial acetic acid. Monitoring is effected by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored in the refrigerator at approximately 5° C. for 24 hours. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.97 g (45% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:24])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([OH:19])[CH:13]=1)[CH:9]=[C:8]([C:20]([OH:22])=[O:21])[C:7]2=[O:23].[CH3:26][NH2:27]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:27][CH3:26])=[C:4]([F:24])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([OH:19])[CH:13]=1)[CH:9]=[C:8]([C:20]([OH:22])=[O:21])[C:7]2=[O:23]
Reactant: O=C(O)c1cn(-c2ccc(F)c(O)c2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(O)c3)c2c1Cl
Temperature: 25 °C
Reaction time: 63 h
Yield: 98.7 %

Procedure:
8-Chloro-6,7-difluoro-1-(4-fluoro-3-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and an aqueous solution (about 40%; 600 mg) of methylamine were added to pyridine (1,500 mg), and the mixture was stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (4 ml) was added to the resultant residue, and the mixture was heated under reflux for 30 minutes. The reaction mixture was allowed to cool, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (305 mg) as a colorless powder.
Reaction SMILES: Br[CH:2]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O-])=[O:19].[Na+]>CO>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([CH:2]([OH:19])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:17]
Reactant: O=C[O-]
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(O)C(=O)c1ccccc1Cl
Yield: 100.2 %

Procedure:
A mixture of methyl 4-bromo-4-(chlorobenzoyl)butyrate (89.5 g), sodium formate (76.2 g) and methanol (400 ml) was stirred under reflux for 12 hours. The reaction mixture was concentrated, and water was added to the resulting residue and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The solvent was evaporated to give methyl 4-(chlorobenzoyl)-4-hydroxybutyrate (72.0 g, 100%) as an oily substance. This oily substance (72.0 g) was dissolved in tetrahydrofuran (400 ml), pyridine (22.2 g) was added thereto, and thereafter phenyl chlorocarbonate (43.8 g) was dropwise added thereto with cooling with ice. After the reaction mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture and then extracted with ethyl acetate. The ethyl acetate layer was washed with 2N hydrochloric acid and then with water, and dried (MgSO4). The solvent was evaporated, and the crystals thus precipitated were collected by filtration to obtain methyl 4-(4-chlorobenzoyl)-4-phenoxycarbonyloxybutyrate (61.2 g, 58%). This was recrystallized from methanol to give colorless prisms. mp 97-98° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([O:18]C)=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:14][CH2:15]2)[C@H:11]([C:16]([OH:18])=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](C2CC2)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 2.66 g of methyl (4S,5R)--3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylate in 60 ml of methanol is added dropwise a solution of 255 mg of lithium hydroxide in 30 ml of water under ice-cooling. The reaction mixture is warmed to room temperature, stirred for one hour and evaporated under reduced pressure to remove methanol. Chloroform is added to the residue. The pH of the mixture is adjusted to about pH 2 with 10% hydrochloric acid under ice--cooling thereto. The chloroform layer is washed with brine, dried, and evaporated under reduced pressure to remove the solvent to give 2.65 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18]O)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18][O:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[CH2:15][O:14]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reaction time: 3 h
Yield: 84.4 %

Procedure:
Nitrogen was bubbled in a solution of 4-hydroxy-3,5-dimethylbenzonitrile (5.0 g, 34.0 mmol) and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (9.53 ml, 76 mmol) in THF (125 ml) at room temperature. The solution was made in a 500 ml flask w/3 necks fitted with a reflux condenser for 10 min. To this was added triphenylphosphine (20.05 g, 76 mmol) in one portion. Nitrogen was bubbled for an additional 10 minutes, followed by the dropwise addition of diethyl azodicarboxylate (12.04 ml, 76 mmol). The color of the reaction mixture changed from pale to a dark reddish brown and the reaction was exothermic. The reaction vessel was immersed in a preheated oil bath held at 65° C. The reaction was found to be nearly complete after 3 h. The contents of the reactor were cooled and evaporated. The semi solid residue was taken in ether and washed with water. The aqueous layer was extracted with ether (2×). The combined organic layer was then washed with brine. It was then dried over anhydrous MgSO4., and then concentrated. Triphenylphosphineoxide was crystallized out and filtered with ether and hexanes. The product was purified on a 330 g ISCo cartridge eluted with 0 to 30% EtOAc-hexanes. (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3,5-dimethylbenzonitrile (7.49 g, 28.7 mmol, 84% yield) was obtained as a clear oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.27 (2H, s), 4.38-4.49 (1H, m), 4.08-4.19 (1H, m), 3.88 (1H, ddd, J=8.18, 5.99, 1.87 Hz), 3.73-3.84 (2H, m), 2.25 (6H, s), 1.41 (3H, s), 1.36 (3H, s).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH:24]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Oc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of 4-phenoxy aniline (100 mg, 0.54 mmol) in dichloroethane (1.5 mL) was added a solution of N-(t-butoxycarbonyl)-D-prolinal (118 mg, 0.594 mmol) in dichloroethane (1.5 mL) at 0-5° C. Sodium triacetoxyborohydride (194 mg, 0.92 mmol) was added to the above solution. Acetic acid (32 mg, 0.54 mmol) in dichloroethane (1 mL) was added dropwise, over a period of 5 min at 0-5° C. The reaction mixture was stirred at 0-10° C. for 3 h. The mixture was diluted with saturated aq NaHCO3 and extracted with dichoromethane. Organic layer was dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (155 mg, 78%); MS; m/z 369 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[C:13]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])([F:15])[F:14]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[F:14])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: Cc1ccc(I)c([N+](=O)[O-])c1
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1[N+](=O)[O-]

Procedure:
Commercially available 4-iodo-3-nitrotoluene was reacted with diethyl bromodifluoromethylphosphonate under Cd coupling conditions using Example 25 to yield diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate (500 mg, 1.55 mmol) was dissolved in EtOAc (10 mL) and EtOH (10 mL). Five percent Pd-C (approximately 20 mg) was added and the mixture placed under H2 (1 atm.) and stirred at room temperature overnight. The mixture was then filtered and concentrated in vacuo to give diethyl(4-methyl-2-aminophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-amino-phenyl)difluoromethylphosphonate was converted to diethyl (2-iodo-4-methylphenyl)-difluoromethylphosphonate using Example 86. Compound 95 was synthesized from this corresponding diethyl phosphonate using procedures similar to those of Example 40. MS (ES-): m/z 347.1 (M−H). 1H NMR: (CD3OD, 400 MHz) δ 7.90 (s, 1H), 7.49 (dd, J=0.8, 8.2, 1H), 7.27 (d, J=8.2, 1H), 2.31 (s, 3H).
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>ClCCl>[Si:17]([O:4][CH2:3][CH2:2][S:1][CH2:5][CH2:6][OH:7])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCSCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCSCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
In dichloromethane (200 ml) were dissolved 2,2′-thiodiethanol (10.0 g, 81.8 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (15.0 ml, 57.7 mmol) at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. After concentration under reduced pressure, diethyl ether was added to the residue. Then, the insoluble matter was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure, whereby the title compound (11.3 g, 31.3 mmol, 54%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([OH:52])[C:48]([F:51])([F:50])[F:49])=[C:43]([N:53]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[N:54]2)[CH:42]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:52][C@H:47]([C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][C:43]=2[N:53]2[CH:57]=[CH:56][C:55]([C:58]([F:59])([F:60])[F:61])=[N:54]2)[C:48]([F:50])([F:51])[F:49])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: O[C@H](c1ccc(Cl)cc1-n1ccc(C(F)(F)F)n1)C(F)(F)F
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2ccc(C(F)(F)F)n2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 39).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH2:20]([O:22][P:23]([O-:27])[O:24][CH2:25][CH3:26])[CH3:21].C(N(CC)CC)C>[Pd].CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([P:23]([O:24][CH2:25][CH3:26])([O:22][CH2:20][CH3:21])=[O:27])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(I)cc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(P(=O)(OCC)OCC)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
1.46 g of 6-iodo-beta-carboline-3-carboxylic-acid-ethylester is added anhydrously to a mixture of 608 g of diethylphosphite, 448 g of triethylamine, 240 mg of palladium tetrakristriphenylphosphine and 60 ml of N-methyl-2-pyrrolidone and is stirred for 12 h at 90° C. After concentration is an oil pump vacuum, the residue is chromatographed on 75 g of silica gel with methylene-chloride/acetone in the ratio of 1/1 as the eluant. The corresponding consolidated fractions are chromatographed on 25 g of silica gel with methylene-chloride/ethanol=10/2 as the eluant. 421 mg of 6-diethoxyphosphoryl-beta-carboline-3-carboxylic-acid-ethylester in the form of an oil is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][C:12](=[O:21])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:21])[CH2:13][CH2:14][N:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)N1CCC(=O)C=C1Cc1ccc(Cl)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC(=O)CC1Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
Intermediate 9 (0.176 mol) in THF (880 ml) was stirred under a N2 flow, and cooled to −78° C. L-selectride (0.264 mol) was added dropwise at −78° C. The reaction mixture was stirred for 1 hour, then poured out into water. DIPE was added. The organic layer was separated, washed with an aqueous NaHCO3 solution, with an aqueous NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 20.2 g (34.8%) of (±)-ethyl 2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylate (intermediate 10).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:21][CH:22]=1.[I:28]I>O1CCCC1.CCCCCC>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH2:24][CH:25]2[CH2:26][CH2:27]2)=[C:21]([I:28])[CH:22]=1
Reactant: II
Reactant: Clc1ccc(OCC2CC2)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1cc(I)c(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 0.988 mL 2,2,6,6-tetramethylpiperidine in 10 mL tetrahydrofuran was added 3.534 mL of a 1.6M solution of n-butyl lithium in hexane at ambient temperature and the mixture was stirred at room temperature for 30 min. To this solution was added rapidly a pre-cooled (−75° C.) solution of 0.300 g 3-chloro-6-cyclopropylmethoxy-pyridazine in 10 mL tetrahydrofuran at −75° C. After 5 minutes, a precooled solution of 0.701 g iodine in 10 mL THF was added rapidly. The reaction mixture was stirred at −75° C. for 30 minutes and then quenched with a saturated aqueous solution of ammonium chloride and diluted with ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.206 g of the title compound as light yellow solid, MS 310.9 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[Br:21][C:19]1[CH:20]=[C:15]([C:13]2[S:14][C:8]3[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)[CH:16]=[N:17][CH:18]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3cncc(Br)c3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3cncc(Br)c3)sc2c1O
Temperature: 25 °C
Yield: 24.4 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (49 mg, 0.13 mmol) and glycine (193 mg, 2.57 mmol) in 0.5 M sodium methoxide/methanol (4.9 mL) was refluxed for 36 h before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (15 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (2 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (13 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.34 (br s, 1H), 12.83 (br s, 1H), 9.46 (t, 1H), 9.30 (d, 1H), 8.91 (m, 2H), 8.73 (m, 1H), 4.02 (d, J=5.8 Hz, 2H); MS: (+) m/z 408.93, 410.87 (M+1, 79Br/81Br).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][C:34]1[S:35][C:36]([S:40](Cl)(=[O:42])=[O:41])=[C:37]([CH3:39])[N:38]=1>ClCCl>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([S:40]([C:36]5[S:35][C:34]([CH3:33])=[N:38][C:37]=5[CH3:39])(=[O:42])=[O:41])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-((2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine hydrochloride (Intermediate 15, 0.050 g, 0.153 mmol), dichloromethane (1.5 mL), and triethyl amine (0.043 mL, 0.306 mmol) was added 2,4-dimethyl-thiazole-5-sulfonyl chloride (0.049 g, 0.229 mmol) and the reaction stirred at room temperature for 2 hours. The solution was concentrated and purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes to afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]5[CH2:21][CH2:22][CH:23]([C:25]([OH:27])=O)[CH2:24][C:19]=5[S:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:25]([CH:23]2[CH2:22][CH2:21][C:20]3[C:13]4[C:12]([NH:11][C:9]5[CH:8]=[CH:7][C:5]6[NH:6][C:2](=[O:1])[S:3][C:4]=6[CH:10]=5)=[N:17][CH:16]=[N:15][C:14]=4[S:18][C:19]=3[CH2:24]2)=[O:27])[CH2:31][CH2:30]1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C2CCc3c(sc4ncnc(Nc5ccc6[nH]c(=O)sc6c5)c34)C2)CC1

Procedure:
76.4 mg (192 μmol) (RS)-4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to example 2) were transformed in analogy to example 3 using 1-methylpiperazine to give after working up and purification 66.5 mg (69%) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17](C=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: O=CC1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: c1cc(N2CCC(NC3CCCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 18 and cyclohexylamine.