Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=1>C(=O)(OCC)OCC>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 8 h

Procedure:
NaH (1.2 g, 60% dispersion in mineral oil) was added to the product of Step A dissolved in diethyl carbonate (10 mL). The reaction mixture was stirred overnight and then cautiously quenched by careful addition to saturated aqueous ammonium chloride solution. The quenched reaction mixture was extracted with ethyl acetate, and the separated orgranic phase was dried and concentrated under vacuum to yield 2.1 g of the title compound containing approximately 30% diethyl carbonate. 1H NMR (CDCl3) δ 7.74 (s, 1H), 7.57 (d, 1H), 7.35-7.55 (m, 5H), 4.57 (s, 1H) 4.19 (q, 4H), 1.29 (t, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:39])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>ClCCl>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:28]([O:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:39])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20.0 g (69.6 mmol) of the compound from Example 2A were dissolved in 1.0 l of dichloromethane and admixed at 0° C. with 14.1 g (139 mmol) of triethylamine. Subsequently, 14.0 g (69.6 mmol) of 4-nitrophenyl chlorocarbonate were added dropwise. The reaction mixture was stirred at 0° C. for 2 h and then at RT for 16 h. For workup, the mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. This gave 31.3 g of crude product, which was reacted without any further purification steps.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([O:23]C)=[O:22])=[CH:19][N:18]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COC(=O)C(C)(C)C)c2ccc(F)cc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.3 %

Procedure:
A mixture of methyl 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.24 g, 0.546 mmol), KOH (0.611 g, 10.9 mmol), water (4 mL) and dioxane (10 mL) was stirred at 100° C. for 5 hours. Then the reaction mixture was cooled to room temperature and treated with 1N HCl to pH=2. The solvent was evaporated at 40° C. under reduced pressure and the residue was triturated with water (10 mL), then decanted and dried at 40° C. under reduced pressure to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.161 g, 94.8%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 12.87 (s, 1H), 12.28 (s, 1H), 9.05 (s, 1H), 8.82 (dd, 1H, J1=9.0 Hz, J2=5.7 Hz), 8.48 (d, 1H, J=2.7 Hz), 7.61 (dd, 1H, J1=10.2 Hz, J2=2.7 Hz), 7.15 (t, 1H, J=12.0 Hz), 4.12 (s, 3H). LCMS: 312.0 [M+H]+, 334.0 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cn2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A suspension of 5-bromo-2-bromomethyl-pyridine (1.34 g, 5.34 mmol), thiomorpholine 1,1-dioxide (0.860 g, 6.36 mmol), and potassium carbonate (1.49 g, 10.8 mmol) in acetone (15.0 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature and the volatiles were evaporated. The residue was partitioned between EtOAc (100 mL) and saturated aqueous ammonium chloride (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 4-(5-bromo-pyridin-2-ylmethyl)-thiomorpholine 1,1-dioxide as a white solid (1.37 g, 84%). m.p.=129-131° C.; LCMS (m/e) 305 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.64 (d, 1H, J=2.3 Hz), 8.82 (dd, 1H, J=2.3 and 8.3 Hz), 7.29 (d, 1H, J=8.3 Hz), 3.78 (s, 2H), 3.13-3.02 (m, 8H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C(N(CC)CC)C>C(#N)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.[Cu]I>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 80.9 %

Procedure:
The (4-benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (1.0 g, 2.04 mmol) was reacted with trimethylsilylacetylene (8.0 ml, 5.56 g, 5.66 mmol), triethylamine (5.0 ml, 3.63 g, 3.58 mmol), bis(triphenylphosphine)palladium (II) chloride (0.10 g, 0.14 mmol) and copper(I)iodide (0.10 g, 0.53 mmol) at room temperature in acetonitrile (15 ml) under a nitrogen atmosphere overnight. Purification by silica gel chromatography (eluting with 50% i-hexane/EtOAc) gave the title compound as an off-white solid (0.70 g, 1.65 mmol, 81%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Li+].CC([N-]C(C)C)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:9]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccccc1
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
Ethyl acetoacetate (2.32 g, 20 mmol) is added to a pre-cold solution of LDA (2.0 M, 20 mL, 40 mmol) in THF (100 mL) at 0° C. After addition, the mixture is stirred for 30 min, then benzyl bromide (3.42 g, 20 mmol) is added dropwise. After stirred at 0° C. for 30 min, the reaction is quenched by 5 N HCl, extracted with ethyl ether. The combined organic layers are washed with water and brine until it is neutral. Concentration and column chromatography yields 1.6 g of the title compounds.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:8]1[CH:9]=[C:4]([CH:3]=[N:2][OH:1])[C:5](=[O:11])[NH:6][C:7]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(C=NO)c(=O)[nH]1
Product: O=c1[nH]c(=O)n(Cc2ccccc2)cc1C=NO

Procedure:
substituting 5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione and benzyl bromide gave 1-benzyl-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione, m.p. 172°-174° C.; and
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14].C(N(CC)CC)C>CN(C=O)C>[CH:11]([C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([C:19]3[S:20][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=3)=[N:3][C:4]=12)=[O:12]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1cnn2ccc(-c3ccc(C(=O)O)s3)nc12
Temperature: 100 °C
Yield: 22 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (590 mg, 3.25 mmol) in DMF was added 5-Carboxythiophene-2-boronic acid (670 mg, 3.9 mmol), triethylamine (1.13 mL, 8.11 mmol) and dichloro-((bis-diphenylphosphino)ferrocenyl)palladium(II) dichloromethane adduct (120 mg, 0.16 mmol). The reaction mixture was degassed with nitrogen then heated at 100° C. for 2 hours. The mixture was cooled to room temperature, diluted with 1N HCl, and filtered. The collected solid was washed with 1N HCl and dried under vacuum. The desired product, 5-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid, was recovered in 22% yield and used for the next step without further purification. LCMS (M+1=274)
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5]I.[OH-].[K+].C1C=CC(C(C2C=CC=CC=2)=[N:20][CH2:21][C:22]#[N:23])=CC=1>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[NH2:23][CH:22]([CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([F:10])([F:9])[F:1])[C:21]#[N:20]
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)C(F)(F)CCI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC(N)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 1,1,1,2,2-pentafluoro-4-iodobutane (2.00 g, 7.30 mmol) in CH2Cl2 (5.99 mL), potassium hydroxide (11 N aq.) (11.95 mL, 131 mmol) and benzyltriethylammonium chloride (0.166 g, 0.730 mmol) were added to a stirred solution of N-(diphenylmethylene)aminoacetonitrile (1.608 g, 730 mmol) in DCM (6 mL) at 25° C. The resulting two-phase mixture was stirred at 25° C. for 4 days. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The resulting residue was mixed with Et2O (72 mL) and 1N aq. HCl (72 mL) and stirred at room temperature for 2 days. The aqueous layer was separated and made alkaline with 5N aq. NaOH solution and the resulting oil was taken up in DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo to afford the desired product, as an oil. 1H NMR (500 MHz, CHCl3-d): δ 3.75 (br s, 1H); 2.41-2.17 (m, 2H); 2.11-4.97 (m, 2H); 1.50 (br s, 2H). m/z=203.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:24]=2)=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Product: N#Cc1cc(F)ccc1-c1cccc(-c2ccnc3nc(C(F)(F)F)ccc23)c1
Yield: 25.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (91 mg, 0.28 mmol) as described in Example 7 part g), affording 4-fluoro-3′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (22 mg, 26%). δH (360 MHz, CDCl3) 7.39-7.45 (1H, m), 7.51-7.76 (7H, m), 7.87 (1H, d, J 8.4), 8.71 (1H, d, J 8.4), 9.29 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O.O1CCOCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:4]2[C@@H:3]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]([CH3:14])([CH3:1])[O:6][C:5]2=[O:7])=[CH:18][CH:17]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(Br)cc2)[C@H]1c1ccccc1
Yield: 51.1 %

Procedure:
To a round bottom flask were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (2.00 g, 10.46 mmol)(commercially available from Sigma-Aldrich, Milwaukee, Wis.), 1,4-dibromobenzene (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (4.93 g), 1,4-dioxane (41.8 mL) and tribasic potassium phosphate (11.10 g, 52.3 mmol). The vessel was purged with nitrogen and then N,N′-dimethylethylenediamine (2.251 mL, 20.92 mmol) and copper (I) iodide (1.992 g, 10.46 mmol) were added. The vessel was heated at reflux overnight providing an orange suspension containing product along with two other major impurities according to LC-MS. To the mixture was added water, and the resulting slurry was transferred to a separatory funnel and extracted with EtOAc (2×). The combined organic layers were back extracted with water, separated, dried with Na2SO4, filtered, and dried under reduced pressure. The residue was purified twice using a 50 g SNAP column ramping EtOAc in heptane from 0-30% leading to coelution of product with impurity. Another run using DCM:MeOH:NH4OH (90:10:1) in DCM afforded (S)-3-(4-bromophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1.85 g, 5.34 mmol, 51.1% yield) as a white solid. Minor amounts of (S)-5,5-dimethyl-4-phenyloxazolidin-2-one was still present after the second purification, but the material was used as is. 1H NMR (400 MHz, DMSO-d6) δ=7.50-7.41 (m, 4H), 7.40-7.34 (m, 2H), 7.33-7.28 (m, 2H), 7.26-7.20 (m, 1H), 5.46 (s, 1H), 1.62 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[N+:8]([C:7]1[C:2]([NH:18][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cccnc1NCc1ccccn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 50 parts of 2-chloro-3-nitropyridine, 32.5 parts of 2-pyridinemethanamine, 53 parts of sodium carbonate and 675 parts of N,N-dimethylacetamide was stirred for 1 hour at 100° C. The reaction mixture was cooled and filtered over Hyflo. The filtrate was poured onto 1000 parts of water and the whole was stirred overnight at room temperature. The product was filtered off and dried, yielding 56.4 parts of N-(3-nitro-2-pyridinyl)-2-pyridinemethanamine; mp. 113.6° C. (intermediate 3).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][O:8]C2CCCCO2)=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:17]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][OH:8])=[CH:15][CH:16]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: OCCc1ccc(N2CCCC2)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 2-(4-bromophenethoxy)tetrahydro-2H-pyran (28.01 g, 98.39 mmol) in toluene (100 ml) and pyrrolidine (9.93 ml, 119 mmol) were added to a mixture of dry palladium acetate (270 mg, 1.20 mmol), 2-(di-t-butylphosphino)biphenyl (720 mg, 2.40 mmol) and sodium t-butoxide (14.42 g, 150 mmol), and they were stirred at 70° C. for 12 hours. Water was added to the reaction mixture. After the extraction with ethyl acetate, the product was extracted from the organic layer with 1 M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried to obtain 4-pyrrolidinophenethyl alcohol in the form of a light yellow solid (16.41 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:16]=[C:15]1[CH2:27][C:28](OCC)=[O:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28](=[O:29])[CH2:27][C:15]2[N:14]([CH3:13])[C:19](=[O:20])[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(CC(=O)Nc2ccc(F)cc2)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.135 ml of 4-fluoroaniline and 0.670 ml of a 2M solution of trimethylaluminium are added, dropwise, to a solution of 190 mg of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 10 ml of toluene. After stirring for 30 minutes at ambient temperature, 10 ml of toluene are added. After stirring for 4 hours at ambient temperature, the reaction mixture is poured into water and a 1M solution of potassium phosphate is added. The precipitate is filtered through sintered glass and then rinsed with ethyl acetate. The filtrate is then washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is extracted and then dried over magnesium sulphate, filtered through sintered glass, and concentrated under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05, V/V), 20 mg of N-(4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:15])[OH:14])[S:11][C:7]=2[C:6]([C:16]2[N:17]=[C:18]([NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:19][CH:20]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>Cl.CO>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13](=[O:14])[OH:15])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]=1
Reactant: COc1ccc(-c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c2sc(NC(=O)O)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2csc(N)n2)c2sc(NC(=O)O)nc12
Temperature: 25 °C

Procedure:
0.070 g of {4-methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-carbamic acid methyll ester (0.00012 Mol) were heated to reflux in 2 ml of 2.5 M HCl/MeOH for 4 hrs. After cooling to room temperature the pH was adjusted to 7 upon drop wise addition of sat. NaHCO3. A precipitate formed, which was filtered off, washed with ethyl acetate and dried. The title compound was obtained as a white solid (23%), F.p.: 293-296° C. (dec.).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)c1ccccc1
Product: COc1ccccc1C1(N[C@H](C(=O)N(C)C)c2ccccc2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.45 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.92 g of the compound obtained in Step 87-2 (5.16 mmol, crude form) as starting materials, 1.09 g (Isomer A, colorless amorphous) and 1.31 g (Isomer B, colorless amorphous) of the respective diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1)[NH2:13]
Reactant: COCc1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCc1ccc(NN)nc1

Procedure:
2.2 g (14.0 mmol) of the compound from Example 12A are initially charged in 10 ml of ethanol. 7.0 g (140.0 mmol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The reaction mixture is then reacted again in a single-mode microwave oven (CEM Explorer) at 150° C. for 2 h. The mixture is then concentrated on a rotary evaporator, taken up in ethyl acetate, washed once with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated again, and the residue is dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]Cl>O>[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=2[S:11]([OH:14])(=[O:12])=[O:13])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CCCc1ccc(N)c(S(=O)(=O)O)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 67.9 %

Procedure:
To 500 ml of water are added 50.0 g of 2-amino-5-n-propylbenzenesulfonic acid and 6.28 g of sodium carbonate and the mixture was dissolved by heating. To the solution was added 88.13 g of bis(2-chloroethyl)amine hydrochloride and the mixture was refluxed by heating for 3 hours, And then, a suspension containing 26.25 g of sodium carbonate suspended in 63 ml of water was added thereto, and the mixture was refluxed by heating for 12 hours. The reaction mixture was condensed under reduced pressure, extracted with methyl alcohol and then methyl alcohol was removed under reduced pressure. To the residue was added 200 ml of water, and after a pH of the mixture was adjusted to about 8.0 with sodium carbonate, 500 ml of chloroform was added thereto and the mixture was stirred. Precipitated crystals were collected by filtration, washed with chloroform and dried to give 44.83 g (yield: 67.9%) of the above title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](O)[CH:6]=[CH:5][CH:4]=1.[OH:10][CH:11]1[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=2)[CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:10][CH:11]2[CH2:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=3)[CH2:14]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Reactant: COc1cccc(O)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OC2CN(c3ccc([C@H](C)NC(C)=O)cc3)C2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 13 mg (0.10 mmol) 6-methoxy-pyridin-2-ol in THF (1.0 mL) is added 23 mg (0.10 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in THF (1.0 mL). 29 mg (0.11 mmol) triphenylphosphine and 25 mg (0.11 mmol) di-tert-butyl azodicarboxylate are added and the mixture is stirred for 3 h at 60° C. Another portion of 29 mg (0.11 mmol) triphenylphosphine and 25 mg (0.11 mmol) di-tert-butyl azodicarboxylate are added and stirring is continued for 2 h at 60° C. The mixture is concentrated in vacuo and the residue is purified by HPLC (XBridge, acetronitrile/H2O (+0.1% NH4OH)) to yield the desired product.