Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15][CH2:14]3)=[O:12])[N:8]2[C:36]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[CH:37]=2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][CH2:27]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Br)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 42, step 1) and 2-chloropyridine-4-boronic acid. The title compound was obtained in 20% yield as light yellow oil. MS (m/e): 595.1 (MH+, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[OH-].[Na+].O>C1(C)C=CC=CC=1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 NH2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.Cl.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH:11]3[N:16]([CH3:17])[CH:14]([CH2:13][CH2:12]3)[CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(O)CC3CCC(C2)N3C)cc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C2=CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 3-(4-methoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (2 g, 8 mmol), glacial acetic acid (6.4 mL) and concentrated hydrochloric acid (6.4 mL). The free base of the title compound was dissolved in ethanol (96%) and added fumaric acid (0.8 g, 6.9 mmol), no precipitate appeared, the solution was concentrated to dryness, the residue was crystallised from absolute ethanol. Yield 1.1 g (40%) as white crystals m.p. 167.3-168.7° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[N+:7]=1[O-:8].[NH3:13]>C(O)C>[NH2:13][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[N+:7]=1[O-:8]
Reactant: N
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])cc(N)[n+]1[O-]
Yield: 41 %

Procedure:
A reaction solution consisting of 5.66 g. (0.03 mole) 6-chloro-4-nitro-2-picoline-1-oxide and 100 ml. ethanol was saturated with anhydrous ammonia and sealed in a strong bottle. This reaction mixture was heated and maintained at a temperature in the range of 100° to 105° C. for 21 hrs. The bottle and contents were then cooled and the seal was broken. Crystals had formed. The crystals were collected on a filter and washed with a small amount of cold ethanol. Recrystallization from 95% aqueous ethanol yielded 2.06 g. (41% yield) of 6-amino-4-nitro-2-picoline-1-oxide as yellow needles having a melting point at 221° to 222° C. (with decomposition). When a small sample was mixed with ethanolic ferric chloride a blue solution was obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7]1[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH3:2].[C:17]1([C:23]2[O:24][C:25]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:28](O)=[O:29])[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7]1[N:12]=[CH:11][C:10]([NH:13][C:28]([C:26]2[N:27]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:24][C:25]=2[C:31]([F:33])([F:34])[F:32])=[O:29])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOCCN(C)c1ncc([N+](=O)[O-])cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCOCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 2.1 %

Procedure:
(2-Ethoxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (150 mg, 0.663 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (179 mg, 0.696 mmol), Et3N (466 uL, 3.3 mmol) and BOP (308 mg. 0.696 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-ethoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide as a yellow solid (6 mg). ES-MS calcd for C20H20F3N5O3 (m/e) 435.41, obsd 436.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:31][CH:32]=3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH:32]=3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-carboxylate (0.037 g, 0.065 mmol) in dichloromethane (1 mL) and the resulting solution was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15% methanol in dichloromethane) to give the title compound as a white solid (0.012 g, 0.025 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.39 (s, 1 H), 7.19-7.12 (m, 4 H), 6.20 (d, J=6.8 Hz, 1 H), 6.11-6.08 (m, 1 H), 4.82-4.74 (m, 1 H), 4.29-4.09 (m, 2 H), 3.98-3.70 (m, 2 H), 3.46-3.34 (m, 3 H), 2.70-2.48 (m, 3 H), 2.16-1.98 (m, 3 H), 2.00 (d, J=7.2 Hz, 3 H); MS: (ES) m/z calculated for C25H27Cl2N4O [M+H]+ 469.2, found 469.4.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[S:7]([CH:11]([NH2:15])[C:12]([OH:14])=[O:13])([OH:10])(=[O:9])=[O:8].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C.C(OC(=O)C)C>[S:7]([CH:11]([N:15]1[CH:18]=[CH:22][CH:21]=[CH:20]1)[C:12]([OH:14])=[O:13])([OH:10])(=[O:9])=[O:8]
Reactant: COC1CCC(OC)O1
Reactant: NC(C(=O)O)S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)C(n1cccc1)S(=O)(=O)O

Procedure:
To a solution of sodium acetate (0.1 mole) in about 300 ml of glacial acetic acid is added about 0.05 mole of α-sulfo-α-aminoacetic acid hydrochloride. The solution is heated to reflux for 5 minutes, 2,5-dimethoxytetrahydrofuran (1 equivalent based on α-sulfo-α-aminoacetic acid hydrochloride) is added as quickly as possible, and the solution refluxed for an additional 2 minutes. The acetic acid is flash evaporated leaving a residue which is taken up in ethylacetate. The ethyl acetate is filtered, dried and evaporated to give α-sulfo-α-(1-pyrryl) acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc2cccnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 44.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (1.4 g, 9.72 mmol), 4-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 448) (2.97 g, 12.6 mmol), pyridine (7 ml) DMAP (cat.) and DCM (30 ml) gave the title compound (1.5 g, 45%), after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH:32]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[NH:31][C:30]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[C:47][Si](C)(C)C)=[CH:42][C:41]=3[O:52][CH2:53][CH3:54])=[N:29]2)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]2[CH:32]([C:33]3[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=3)[NH:31][C:30]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[CH:47])=[CH:42][C:41]=3[O:52][CH2:53][CH3:54])=[N:29]2)=[CH:26][CH:27]=1
Reactant: CCOc1cc(C#C[Si](C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OCC)c1
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrahydrofuran (3.45 mL, 3.45 mmol) was added dropwise to a solution of methanol (1.33 mL) and 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-trimethylsilanylethynylphenyl)-4,5-dihydro-1H-imidazole (3.50 g, 6.90 mmol) in tetrahydrofuran (70 mL) cooled in an ice bath. After stirring for 30 min, the reaction mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with methylene chloride (300 mL, 2×100 mL). The combined organic phases were dried over magnesium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluting with 2% methanol in chloroform) to give 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethynylphenyl)-4,5-dihydro-1H-imidazole as a yellow foam (2.66 g, 89%). LC-MS: 435.2 [(M+H)+].
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 100 °C
Yield: 48.3 %

Procedure:
Chlorosulfonic acid (10 ml, 0.15 mol) is added dropwise slowly to acetanilide (4 g, 0.029 mol). The mixture is then heated to 100° C. for one hour. The oil that forms is cooled and carefully poured onto ice. The resulting precipitate is collected by filtration affording the desired product (3.4 g, 0.014 mol, 48% yield). The sulfonyl chloride is used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([O:21]C)[CH:15]=[C:14]([O:23]C)[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([OH:21])[CH:15]=[C:14]([OH:23])[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32]
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OC)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(O)cc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 103 (0.25 g, 0.54 mmol) was demethylated using pyridine hydrochloride (4.0 g, 34.6 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[N:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].[CH3:18][N+:19]([CH3:21])=[CH2:20].[I-].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][N:2]([CH3:1])[C:3]([C:5]1[C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:14]([OH:16])[C:8]2[N:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: C=[N+](C)C
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(O)c(CN(C)C)c(C(=O)N(C)C)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 800.9 %

Procedure:
To a suspension of 2.0 g (8.6 mmol) 7-Hydroxy-2,3-dimethyl-3H-benzimidazole-5-carboxylic acid dimethylamide in dichloromethane (80 ml) was added dropwise a suspension of 1.7 g (9.4 mmol) Eschenmoser's salt in dichloromethane (50 ml). After stirring for 3 h at room temperature, the reaction mixture was poured into saturated sodium bicarbonate solution (100 ml) and extracted with dichloromethane (2×50 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo to give 20 g (82%) of the title compound as an orange foam. The compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:6]([CH3:9])([Cl:8])[CH3:7])[C:3](=[O:5])[CH3:4].S(Cl)([Cl:14])(=O)=O>ClCCl.C1(NC2CCCCC2)CCCCC1>[Cl:14][CH2:4][C:3](=[O:5])[C:2]([CH3:10])([CH3:1])[C:6]([Cl:8])([CH3:9])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)C(C)(C)C(C)(C)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC(C)(Cl)C(C)(C)C(=O)CCl
Temperature: 20 °C
Reaction time: 24 h
Yield: 62.9 %

Procedure:
After dissolving 8.0 g of 3,3,4-trimethyl-4-chloro-2-pentanone in 30 ml of dichloromethane, two drops of dicyclohexylamine were added, and then 10.0 g of sulfuryl chloride was added dropwise at 0° C. After addition, the reaction solution was stirred at 20° C for 24 hours, poured into ice water and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over magnesium sulfate and concentrated. The residue obtained was column-chromatographed on silica gel to obtain 6.1 g of 1,4-dichloro-3,3,4-trimethyl-2-pentanone (a compound of the foregoing formula (II) wherein a substituent X is a chlorine atom) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:17])[NH:13][CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:18]>>[BrH:18].[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:17])[NH:13][CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(-c2cnc[nH]c2=O)cc1OC
Agent: Br
Product: O=c1[nH]cncc1-c1ccc(O)c(O)c1

Procedure:
5-(3,4-Dimethoxyphenyl)-4(3H)-pyrimidinone (9.28 g) (40 mmol) are refluxed in 300 ml of 48% aqueous hydrogen bromide solution for 48 hours. The suspension obtained is suction filtered, the filter material is taken up in water and the product is precipitated by the addition of sodium hydrogen carbonate. The precipitate is filtered off, washed with water and dried at room temperature. There are obtained 8.3 g of 5-(3,4-dihydroxyphenyl)-4(3H)-pyrimidinone hydrobromide as a beige powder. M.p.>270° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.[C:29]([CH:32]([CH:34]([C:36]([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:29]([O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:32][CH2:34][CH3:36]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCOC1CCNCC1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a solution of 10 g (50 mmol) of 1-t-butoxycarbonyl-4-piperidone (Aldrich) in 10 mL of THF at −78° C. was added 75 mL (75 mmol) of a 1 M solution of diisobutylaluminum hydride in toluene. The reaction mixture was allowed to warm to −20° C. and stirred for 3 h. After this time it was poured into 500 mL of sat'd solution of potassium sodium tartrate tetrahydrate (Rochelle salt), the mixture was stirred vigorously for 20 min, and the layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic fractions were washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the title compound which was used without further purification.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([F:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1F)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
A solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.8 mmol) in DCM (100 mL) was treated with TFA (20 mL) and stirred at RT for 6 h. The mixture was extracted with water and the combined aqueous layers were neutralized with NH3H2O. The precipitate was collected by filtration and dried to give 3-(5-amino-2,4-difluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (661 mg, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.78 (s, 1H), 7.08-6.93 (m, 2H), 6.80 (dd, J=10.2, 8.1 Hz, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 3.50 (s, 3H), 2.84 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 317.0 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O.[N:21]#[C:22][NH2:23].[Na]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11](=[N:23][C:22]#[N:21])[O-:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: N#CN
Reactant: CC(=O)Nc1ccc(N=O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+]([O-])=NC#N)cc1
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
4-(N-acetylamino)nitrosobenzene (15.0 g, 91.5 mmol) and N-bromosuccinimide (16.3, 91.6 mmol) were dissolved in dimethylformamide (150 ml). At ambient temperature, the solution was treated with monosodium cyanamide (9.14 g, 142.8 mmol). After 45 minutes, the brown solution was treated with N-bromosuccinimide (6.4 g, 36 mmol) and stirred for an additional 11/2 hours. The mixture was poured on ice-water (500 ml) and left overnight. The yellow crystallised precipitate was collected and dried to give 16.8 g 4-(N-acetylamino)phenyl-ONN-azoxycyanide as a yellow powder, m.pt. 240°-242° C. (Yield: 90% of theoretical).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][NH:11][C:12]2[S:13][C:14]([CH3:25])=[C:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:16]=2)[CH2:9][CH2:8]1>C1COCC1>[CH:7]1([CH2:10][NH:11][C:12]2[S:13][C:14]([CH3:25])=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[CH:23][CH:24]=3)[N:16]=2)[CH2:9][CH2:8]1
Reactant: Cc1sc(NCC2CC2)nc1-c1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(NCC2CC2)nc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Add a solution of 1M lithium aluminum hydride in THF (4.6 mL, 4.6 mmol) over 5 min to a solution of 4-(2-cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzonitrile (410 mg, 1.52 mmol) in anhydrous THF (10 mL). Heat to reflux for 30 min, cool to room temperature and quench by dropwise addition of water (5 mL), ether (50 mL), 3N NaOH (5 mL) and additional water (15 mL). Stir vigorously for 30 min and filter over a bed of Celite®. Wash the filtrate with water (2×100 mL) and brine (100 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (340 mg, 82%) that was used without further purification. MS (ES+) m/z: 274 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[NH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl>[CH:5]12[CH2:6][CH:1]1[CH2:2][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:27][CH2:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:25])=[CH:9][N:8]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CCNCC2)cc1Cl
Reaction time: 8 h
Yield: 18 %

Procedure:
In THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (128 mg, 0.60 mmol) and HATU (182 mg, 0.48 mmol). DIEA (0.20 mL, 1.2 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h. The reaction mixture was concentrated, followed by addition of water and extraction with DCM. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=50/1) to give a white solid. The product was dissolved in DCM (10 mL), and trifluoroacetic acid (1 mL) was added. The reaction was conducted at ambient temperature for 4 h. Then the reaction mixture was adjusted to a pH of 9 with saturated aqueous sodium bicarbonate. The organic phase was dried and the solvent was removed by rotary evaporation to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(piperdin-4-ylmethyl)pyrimidine-5-formamide (34 mg, 18% yield).