Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][N:12]=1)[N:9]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1cn([C@H]2CCCNC2)c2cnc(Br)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn([C@H]2CCCN(CCN(CC)CC)C2)c2cnc(Br)cc2c1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (5)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,7-naphthyridine-3-carboxylate hydrochloride (Intermediate 62, 610 mg, 1.46 mmol, 1 equiv.) in acetonitrile (4 mL) was added 2-chloro-N,N-diethylethanamine hydrochloride (252 mg, 1.46 mmol, 1 equiv.) followed by potassium carbonate (1 g, 7.32 mmol, 5 equiv.). This was stirred in the microwave at 120° C. for 30 min. The reaction was cooled to room temperature and diluted with ethyl acetate. The precipitate was discarded, and the filtrate was concentrated to provide (S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (mg, %).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[C@H:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][Si:13]([CH3:37])([CH3:36])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[CH:65]=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[C:63](Br)=[CH:62][C:61]=3[Cl:72])=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58](=[O:73])[NH:59][C:60]3[C:61]([Cl:72])=[CH:62][C:63]([C:24]4[CH:23]=[CH:22][C:21]([C:19]5[N:20]=[C:16]([C@H:15]6[N:11]([C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[CH2:12][Si:13]([CH3:37])([CH3:36])[CH2:14]6)[NH:17][CH:18]=5)=[CH:26][CH:25]=4)=[C:64]([O:66][C:67]([F:70])([F:69])[F:68])[CH:65]=3)=[CH:54][N:53]=2)[C@H:48]([CH3:74])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[Si](C)(C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 25.8 %

Procedure:
To a solution of [[(5)-1-((R)-3,3-dimethyl-5-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-[1,3]azasilolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methylester (51.6 mg, 0.096 mmol; Preparation 11) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (56.7 mg, 0.096 mmol) dissolved in toluene (0.61 mL) and water (0.24 mL) was added potassium carbonate (66.0 mg, 0.48 mmol). The reaction mixture was sparged under nitrogen for 15 min and Pd(dppf)Cl2CH2Cl2 (7.02 mg, 0.009 mmol) was added. The reaction mixture was sparged with nitrogen and heated to 90° C. overnight, cooled to RT, diluted with EtOAc, and washed with water and brine to produce a dark colored oil. The residue was purified by silica gel chromatography (12 g silica, 0% to 100% EtOAc/hexane) to produce the title intermediate as a yellowish solid (23 mg; 26% yield) (m/z): [M+H]+ calcd for C44H54ClF3N8O7Si 927.35 found 927.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[N:19]1([CH2:18][CH2:17][CH2:16][S:8][C:5]2[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCCN1CCCCCCC1
Reactant: S=c1ncc(Cl)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnc(SCCCN2CCCCCCC2)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
5-Chloropyrimidine-2-thione (2 mmol) and potassium tert-butoxide (2 mmol) was stirred together in DMF (20 ml) for 5 min at room temperature before 1-(3-chloropropyl)perhydroazocine (2 mmol) was added. The mixture was stirred for 2 days at room temperature and for 2 hours at 80° C. The solution was evaporated, the residue triturated with water, extracted with chloroform and the dried (MgSO4) chloroform solution evaporated. The oily product which remained (0.47 g) was the title compound; yield 45% 1H NMR (CDCl3): 1.3-2.8 (9×CH2), 3.20 (SCH2), 8.40 (H-4, H-6). The compound was further characterized as a solid by conversion into its HCl salt using HCl in ethanol; m.p. 154° C. (acetone).
Reaction SMILES: [NH2:1][C@H:2]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][C@H:2]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(=O)[C@@H](N)Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)[C@H](Cc1ccc(C(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 4-[(2S)-2-amino-3-(ethylamino)-3-oxopropyl]benzoate was dissolved in dichloromethane (3.5 mL). Pyridine (0.05 mL) and acetic anhydride (0.05 mL) were added. The reaction was allowed to stir overnight at room temperature under nitrogen. The reaction was transferred to a separatory funnel and washed with saturated sodium bicarbonate. The aqueous layer was extracted three additional times with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting material was purified by column chromatography. 1H NMR 600 MHz (CDCl3) δ 7.86 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 6.89 (s, 1H), 6.47 (s, 1H), 4.68 (m, 1H), 3.15 (m, 2H), 3.06 (m, 2H), 1.93 (s, 3H), 1.55 (s, 9H), 0.99 (m, 3H). MS: cal'd 335 (MH+), exp 335 (MH+).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[C:31]([NH:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: NNc1cccc2ncccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: O.Cl.[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][OH:25])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:28][C:29](Cl)=[O:30].[OH-].[K+]>O.C1COCC1>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:28][C:29]3=[O:30])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCNCCO)cs1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCCN2CCOCC2=O)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.8 %

Procedure:
To a solution of EXAMPLE 208B (187 mg, 0.44 mmol) in H2O (2 mL)/THF (1 mL) was chloroacetyl chloride (110 mg, 0.97 mmol) in THF (3 mL) dropwise added under a period of 40 min. The temperature was kept at 8° C. and 2 M KOH was added continuously to adjust the pH to around 6-8. Aqueous potassium hydroxide (6 M, 0.38 mL, 1.41 mmol) was added and the mixture was stirred at room temperature for 20 min. The pH was adjusted to 8 and the mixture was extracted with ethyl acetate. The organic phase was separated and the solvent was evaporated. The residue was flash chromatographed on silica gel eluting with 30% acetone in DCM, yielding 98 mg (52 %) of the title compound: MS (Ionspray, [M+H]+) m/z 429. Anal. Calcd. (found) for C17H20ClN3O4S2: C, 47.5 (47.4)%; H, 4.7 (4.9)%; N, 9.8 (9.5)%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:30]#[N:31])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)N1CCC(C(=O)Nc2ccc(C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 83 °C
Reaction time: 6 h
Yield: 18 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.50 g, 0.94 mmol) in N,N-dimethylformamide (6 mL) was added zinc cyanide (70 mg, 0.58 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.04 mmol). The reaction mixture was stirred at 83° C. for 6 h and then at room temperature overnight. It was then partitioned between 3:1 chloroform:isopropanol and ammonium hydroxide and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was suspended in methanol and filtered. The filtered solid was then slurried in diethyl ether and filtered to give 70 mg (18%) of the title compound as white solid. The methanolic filtrate was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-20% 2 M ammonia/methanol solution in dichloromethane. The chromatography product was slurried in methanol and filtered to give an additional 0.14 g (35%) of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>CN(C)C=O>[Br:48][CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCO)c(C)c3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (1.00 g, 2.70 mmol) in anhydrous N,N-dimethylformamide (15 mL) were added triphenylphosphine (0.78 g, 3.00 mmol) and carbon tetrabromide (1.00 g, 3.00 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4-(3-bromo-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 0.60 g (51%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C=O)C>[C:14]1(=[O:23])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1ccncc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 17.8 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 15.52 g (55 mmol) of N-(4-bromobutyl)phthalimide in 80 ml of DMF was added 8.23 ml (5 mmol) of 1,8-diazabicyclo(5.4.0]-7-undecene. The mixture was stirred at room temperature for 7 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.63 g of the desired compound (yield: 17.2%, colorless crystals). mp: 126°-127° C.
Reaction SMILES: [CH:1]([C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1)=[CH2:2].CO.[Br:14]Br.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:14][CH2:2][CH2:1][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: C=CC1(CC(=O)OCC)CC1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 30.86 ml (30.86 mmol) of borane/THF complex solution (1 M in THF) are added dropwise at 0° C. to a solution of 14.00 g (90.79 mmol) of ethyl (1-vinylcyclopropyl)acetate (Example 2A) in 80 ml of anhydrous THF. After 30 min at 0° C., the mixture is stirred at room temperature for a further 30 min, and 0.20 ml (5.00 mmol) of methanol is then added. At −5° C., 5.61 ml (108.94 mmol) of bromine and 26.98 g (150.0 mmol) of sodium methoxide solution (30% strength in methanol) are then successively added dropwise to the reaction mixture. After the mixture has reached room temperature, 30 ml of saturated sodium bicarbonate solution are added. The reaction mixture is extracted three times with tert-butyl methyl ether. The combined organic phases are washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent and kugelrohr distillation of the residue at 180° C. and 0.04 mbar gives 12.90 g (60% of theory) of the title compound as a yellow oil which, on storage in a fridge, turns very dark over a period of a few hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH:2]=1
Reactant: NO
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cccnc1

Procedure:
3-Pyridinecarboxaldehyde oxime was prepared by treating 3-pyridinecarboxaldehyde (10 mL, 106 mmol) with hydroxylamine hydrochloride (8.10 g, 117 mmol) and 50% aqueous sodium hydroxide (2 mL) in ethanol (100 mL) and water (200 mL) for 17 hours. The solution was adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide. The solution was extracted with several portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 8.3 g of a white solid. The aqueous layers were combined and back-extracted with chloroform (5×1 L) to yield additional product. The total amount of 3-pyridinecarboxaldehyde oxime obtained was 12.24 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1Br.[CH3:18][NH2:19]>>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[NH:19][CH3:18]
Reactant: Nc1c(Br)c(=O)[nH]c(=O)n1Cc1ccccc1
Reactant: CN
Product: CNc1c(N)n(Cc2ccccc2)c(=O)[nH]c1=O
Temperature: 5 °C

Procedure:
6-Amino-1-benzyl-5-bromouracil (134 g) was stirred with 40% aqueous methylamine solution (750 ml) for 24 hours. After cooling to 5° C., the precipitate was filtered and dried under suction to provide 6-amino-1-benzyl-5-methylaminouracil (55 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:13]=[CH:12][C:11]=2[CH3:34])=[O:8])=[CH:5][C:4]([CH3:35])=[N:3]1.C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:19]1[C:20](=[N:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([CH3:34])=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:35])[CH:5]=3)=[O:8])[CH:15]=2)=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 72.4 %

Procedure:
In the same manner as in Reference Example 5 and using 1,3-dimethyl-N-{2-methyl-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (2.91 g, 5.92 mmol), N,N-diisopropylethylamine (1.34 mL, 7.70 mmol), iodoacetamide (1.42 g, 7.70 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (2.35 g, 72%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)cc1
Yield: 82 %

Procedure:
As described for example 8e, 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol), was converted, using 4′-fluoro-acetophenone instead of 4-fluorobenzotrifluoride, to the title compound (85 mg, 82%) which was obtained as an off white solid. MS: m/e=362.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:29]>C(Cl)Cl.FC(F)(F)S(O)(=O)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([I:29])[C:7]([NH2:10])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 5 g 6-Amino-nicotinic acid methyl ester and 16.2 g Bis(pyridine)iodonium(I) tetrafluoroborate in 250 mL DCM, 7.6 mL Trifluoromethanesulfonic acid were added dropwise at 0° C. The mixture was stirred for 24 h at RT. Then additional 3.2 g Bis(pyridine)iodoniun(I) tetrafluoroborate and 1.5 mL Trifluoromethanesulfonic acid were added. After stirring for 2 h at RT the reaction mixture was concentrated under reduced pressure and then taken-up with concentrated aqueous Na2SO3 solution and brought to pH 8 with concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with brine and then dried over MgSO4. After filtration the solvent was removed under reduced pressure and the residue was codestilled with 100 mL toluene. Yield: 9.6 g.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([N:15]([CH3:21])[C:16](=O)[CH2:17][CH2:18][CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:16]([N:15]([CH3:21])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]([N:2]([CH3:28])[CH3:1])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)N(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The title compound from step 1 (200 mg, 0.528 mmol) was dissolved in abs. THF (15 mL). LiAlH4 (39 mg, 1.06 mmol) was added in argon. The batch was boiled for 7 h with reflux. The batch was then cooled to room temperature, mixed with THF (12 mL) and H2O (5 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in a vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][N:12]=[C:13]=[S:14]>C(O)(=O)C>[CH3:11][NH:12][C:13](=[S:14])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CN=C=S
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: CNC(=S)Nc1cccc(C(=O)O)c1
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of 279.6 g of 3-amino-benzoic acid, 164.1 g of methyl isothiocyanate and 1000 g of 100% acetic acid is heated to 80-85° C. The temperature rises to 95-100° C. in the course of 20 minutes without further heating, and a clear solution from which the product slowly crystallizes out forms. The suspension is kept at 90-100° C. for 2 hours, subsequently cooled to 15-20° C. and filtered with suction and the material on the suction filter is washed with acetic acid. 404 g of the title compound result, purity: 99.5%, melting point: 190-91° C., decomposition. Yield: 95.7% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C(=O)C.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: ClCCc1ccc(Cl)cc1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.011 g, 160 mmol), N,N-dimethylacetamide (0.748 mL, 7.99 mmol), and toluene (73 mL). The mixture was heated to 65 to 70° C. and then thionyl chloride (12.24 mL, 168 mmol) was added over 1 h. The reaction was stirred at 60 to 68° C. for 2 h to give a dark-brown solution. This solution was cooled to 45° C., washed with water (2×27 mL) and saturated aqueous sodium bicarbonate (3×27 mL) at 40 to 45° C., and then cooled room temperature and allowed to stir overnight.