Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](I)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:38]=[C:37]([CH3:39])[C:36]([CH3:40])=[C:35]1[CH:41]([OH:44])[C:42]#[CH:43])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(N(CC)CC)C.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:43]#[C:42][CH:41]([C:35]3[N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH:38]=[C:37]([CH3:39])[C:36]=3[CH3:40])[OH:44])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(O)c1c(C)c(C)cn1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Oc1cc2c(I)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cn(C(=O)OC(C)(C)C)c(C(O)C#Cc2c(F)ccc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-tert-butoxycarbonyloxy-5-fluoro-4-iodo-indole-1-carboxylic acid tert-butyl ester (from Example 2 above) (1 g, 2.22 mmol), and 3,4-dimethyl-2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester (from Example 45 above) (1.38 g, 5.54 mmol) in dry THF(12 mL) and triethylamine(Aldrich, 12 mL) was degassed by bubbling argon through the solution for 10 minutes. At this time copper(I) iodide (Aldrich, 84.4 mg, 0.44 mmol) and (Ph3P)4Pd (0.25 g, 0.22 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. Flash chromatography (silica gel, 85:15 hexanes/ethyl acetate) afforded 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester as an orange oil. (Yield 0.76 g, 57%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>>[CH3:10][CH:9]([N:12]=[C:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:11]
Reactant: CC(C)N
Reactant: CC1CCC(=O)CC1
Product: CC1CCC(=NC(C)C)CC1
Reaction time: 8 h

Procedure:
To a mixture of 600 g. 4-methyl cyclohexanone and 1 l. isopropylamine are added 500 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the sieves are removed by filtration and the excess of isopropylamine is removed in vacuo at room temperature. The residual oil is 1-methyl-N-(4-methyl cyclohexylidene)-ethylamine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][C:14]1[NH:15][C:16](=[O:24])[C:17]2[CH2:23][O:22][CH2:21][CH2:20][C:18]=2[N:19]=1)C(=O)OC(C)(C)C.Cl>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:13][C:14]1[NH:15][C:16](=[O:24])[C:17]2[CH2:23][O:22][CH2:21][CH2:20][C:18]=2[N:19]=1
Reactant: COCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COCCNCc1nc2c(c(=O)[nH]1)COCC2
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-methoxyethyl((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)carbamate (257 mg, 0.545 mmol) in dioxane (5 mL) was added hydrochloric acid (4M in dioxane, 0.818 mL, 3.3 mmol) and the solution was stirred for 8 h. The precipitate was filtered and washed with ether. The residue was re-dissolved in ether, and stirred overnight (8 h) in ether. The precipitate was filtered and washed with ether to yield the title compound as a hydrochloride salt (107 mg). 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2H) 4.27 (s, 2H) 3.90-4.03 (m, 3H) 3.66-3.77 (m, 2H) 3.43 (s, 3H) 3.35-3.41 (m, 3H) 2.74 (s, 2H). MS (m/z, MH+): 239.3
Reaction SMILES: [F:1][C:2]([F:15])([C:5]([CH2:13][CH3:14])([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:6][CH3:7])[CH:3]=[O:4].[BH4-].[Na+]>C1COCC1.C(O)C>[F:15][C:2]([F:1])([C:5]([CH2:13][CH3:14])([O:8][Si:9]([CH3:10])([CH3:12])[CH3:11])[CH2:6][CH3:7])[CH2:3][OH:4]
Reactant: CCC(CC)(O[Si](C)(C)C)C(F)(F)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)(O[Si](C)(C)C)C(F)(F)CO

Procedure:
A stirred, ice-cooled solution of 2,2-difluoro-3-ethyl-3-trimethylsilyloxy-pentanal (1.45 g, 6.08 mmol) in THF (5 ml) and ethanol (15 ml) was treated with sodium borohydride (2.76 mg, 7.30 mmol). After 30 minutes the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over MgSO4 and concentrated. Flash chromatography (50 g silica gel; 10% EtOac in petroleum ether as eluant) afforded the title compound as a colourless oil, δ 0.15 (s, 9H), 1.36 (t, 6H), 2.48 (m, 1H), 3.93 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.N1CCCCC1>C(#N)C>[CH3:14][O:15][CH:16]([O:19][CH3:20])/[CH:17]=[C:9](/[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])\[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(C=O)OC
Reactant: COC(=O)CS(=O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: COC(=O)/C(=C\C(OC)OC)S(=O)c1ccccc1
Temperature: 60 °C
Yield: 99 %

Procedure:
A mixture of methyl 2-(phenylsulfinyl)acetate (1 g, 5.04 mmol), 2,2-dimethoxyacetaldehyde (3.15 ml, 10.09 mmol) and piperidine (0.999 ml, 10.09 mmol) in acetonitrile (20 ml) was heated to 60° C. for 18 hr. After cooling to rt, the volatiles were removed in vacuo and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-40% EtOAc/Hex gradient. The pure fractions were concentrated to afford (E)-methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate (1.42 g, 4.99 mmol, 99% yield) as a light yellow oil. HPLC retention time=1.23 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+Na)=307.06. 1H NMR (500 MHz, chloroform-d) δ ppm 3.40 (s, 3H), 3.41 (s, 3H), 3.69 (s, 3H), 5.71 (d, J=7.2 Hz, 1H), 7.07 (d, J=6.6 Hz, 1H), 7.48 (m, 3H), 7.66 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH:8]([CH2:11][CH3:12])[CH2:9][OH:10])=[N:3][CH:2]=1.[Br:13]Br.[OH-].[Na+]>C(O)(=O)C>[Br:13][C:5]1[C:4]([NH:7][CH:8]([CH2:11][CH3:12])[CH2:9][OH:10])=[N:3][CH:2]=[N:1][CH:6]=1
Reactant: CCC(CO)Nc1ccncn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(CO)Nc1ncncc1Br
Reaction time: 24 h

Procedure:
2-(4-Pyrimidinylamino)-1-butanol (4.2 g) was dissolved in acetic acid (42 mL), and bromine (1.5 mL) was added dropwise at a normal temperature. After stirred for 1 day at the same temperature, the solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1.1) to give the title compound (4.4 g) as white crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH2:10](N)[CH2:11][NH2:12]>O.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:10][CH2:11][NH:12]1
Reactant: NCCN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CCNO2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts toluene and 595 parts of 50% formalin. A uniform toluene-water dispersion is maintained with agitation. The temperature of the reaction mixture is adjusted to 25° C. and maintained below 30° C. while 144 parts of ethylene diamine are added slowly. The reaction mixture is stirred for 2 hours at 30° C. after the amine addition is complete. The reaction mixture is heated to 46° C. under reduced pressure and refluxed for 3 hours. After 3 hours the distillate is passed through an oil water separator in the distillate return line. The toluene is continuously returned to the reactor while the water is removed. Azeotropic water removal is continued while the batch temperature is increased to 69° C. and the pressure is gradually reduced to about 5.0 kPa. The reaction mixture is essentially water free. It is cooled while 150 parts of 2-butoxyethanol are added and mixed in. The clear pale yellow solution is filtered. The product had the following composition and properties: Percent closed dihydrobenzoxazine 66%; equivalent wt. 224; solids 55.2%; Brookfield viscosity 12 cps @25° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:20]([C:22]4[CH:23]=[C:24]([C:28]5[N:32]=[C:31]([C:33](OCC)=[O:34])[O:30][N:29]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Li+]>C1COCC1>[OH:34][CH2:33][C:31]1[O:30][N:29]=[C:28]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:20]([NH:19][CH2:18][C:12]2([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:21])[N:32]=1
Reactant: CCOC(=O)c1nc(-c2cccc(C(=O)NCC3(c4nc(-c5ccccc5)cs4)CCOCC3)c2)no1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2noc(CO)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
Ethyl 3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (1.0 g, 1.93 mmol) was dissolved in anhydrous THF (20 mL) and the reaction mixture was cooled to 0° C. Lithium borohydride (1.15 mL, 2.3 mmol, 2M in THF) was added, and the reaction mixture was stirred for 30 min, quenched with ice, and diluted with EtOAc. The organic layer was washed with water and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluant: 70-80% EtOAc in petroleum ether) to afford 3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide (300 mg, yield 32%). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (m, 1H), 8.20-8.17 (m, 1H), 7.96 (m, 1H), 7.91-7.88 (m, 2H), 7.62 (m, 1H), 7.53-7.51 (m, 2H), 7.36-7.34 (m, 3H), 4.89 (s, 2H), 3.99-3.92 (m, 2H), 3.90-3.88 (d, J=5.7 Hz, 2H), 3.78-3.70 (m, 2H), 2.35-2.27 (m, 2H), 2.08-2.00 (m, 2H). MS (ESI) m/z: Calculated for C26H24N4O4S: 476.15. found: 475.7 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][C:24](OC)=[O:25])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O.O.[Na+].[K+].C(C(C(C([O-])=O)O)O)([O-])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][OH:25])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nccn1-c1nc(-c2ccc(C(F)(F)F)cc2)c(CCCO)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Methyl 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.00 g) was dissolved in toluene (15 ml). To the obtained solution was added dropwise a mixture of a 70% toluene solution (1.20 g) of sodium dihydrobis(2-methoxyethoxy)aluminate, and toluene (5 ml) at 0° C., which was stirred at 0° C. for 30 minutes. To the reaction mixture was carefully added a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate (50 ml), which was stirred at room temperature for 1 hour. The precipitated crystals were filtered, washed in sequence with a 10% aqueous solution of (+)-sodium potassium tartratesesquihydrate, pure water and isopropyl ether, and air-dried to give crystals of 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropanol (0.75 g, 81%). Recrystallization from ethyl acetate-isopropyl ether gave pale yellow prisms. Melting point 127-129° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[N:23][C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[N:23][C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N=c1[nH]c2ccccc2n1C1CCNCC1

Procedure:
A mixture of 12 parts of N-{1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}acetamide and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and recrystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 2.6 parts of N-[1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-ylidene]acetamide; mp. 164.5° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[CH:3]=1.[CH3:14][C:15]1([CH3:22])[C:19]([CH3:21])([CH3:20])[O:18][BH:17][O:16]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:13])[CH:3]=[C:2]2[B:17]1[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:22])([CH3:14])[O:16]1
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1ccc2c(c1)c(I)cn2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2C
Temperature: 100 °C
Yield: 37.3 %

Procedure:
5-Methoxy-1H-indole (5.15 g, 35.0 mmol) in DMF (100 mL) was stirred with KOH (2.06 g, 36.7 mmol) at room temperature for about 15 min then iodine (9.06 g, 35.7 mmol) was added. The mixture was stirred at room temperature for about 30 min followed by the portion-wise addition of NaH (60% dispersion in mineral oil, 1.67 g, 42.0 mmol). After stirring for about 15 min at room temperature, iodomethane (2.40 mL, 38.5 mmol) was added and the mixture was stirred for about 15 min. The solvents were removed under reduced pressure and the mixture was stirred with water (300 mL) for about 15 min. The slurry was treated with DCM (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL) and the combined organic layers were washed with water (100 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give crude 3-iodo-5-methoxy-1-methyl-1H-indole (9.90 g, 34.5 mmol, 99%) which was used directly. A round bottom flask was charged with 3-iodo-5-methoxy-1-methyl-1H-indole (9.90 g, 34.5 mmol), PdCl2(dppf)-CH2Cl2 adduct (1.408 g, 1.724 mmol), TEA (33.6 mL, 241 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28.7 g, 224 mmol) and 1,4-dioxane (200 mL). The reaction mixture was heated at about 100° C. for about 40 min, cooled to room temperature, and concentrated in vacuo. The material was stirred with EtOAc (300 mL), filtered, and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (120 g column) eluting with 25% EtOAc in heptane to give 5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (3.70 g, 37%): LC/MS (Table 2, Method d) Rt=2.68 min; MS m/z: 288.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(Oc2ccccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-phenoxyphenol (950 mg), potassium carbonate (3.2 g) and 1-bromo-3-chloropropane (2.5 mL) in N,N-dimethylformamide (5 mL) affords 0.50 g of 4-(3-chloropropoxy)-O-phenylphenol used without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>CN(C=O)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:21][CH:22]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cn1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
A mixture 3,4-dinitro-benzoyl chloride (1.78 g, 7.8 mmol) and 5-bromo-2-amino-pyridine (1.35 g, 7.8 mmol) in 20 mL DMF was stirred overnight. After evaporation of the solvent, the residue was purified by chromatography on silica gel (eluent gradient: dichloromethane/methanol 100:0->75:1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH:9]=O.[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH:9]=[CH:8][C:7]4[C:6](=[O:11])[N:5]5[CH2:12][CH2:13][CH2:14][CH2:15][C:4]5=[N:3][C:2]=4[CH3:1])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Cc1nc2n(c(=O)c1CC=O)CCCC2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: Cc1ccccc1
Product: Cc1nc2n(c(=O)c1C=CN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Yield: 97.4 %

Procedure:
A mixture of 2.96 g (14.33 mmoles) of (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)-acetaldehyde (II), 3.16 g (14.33 mmoles) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (IV) and 50 mL of toluene was transferred to a Dean Stark apparatus. The mixture was brought to boiling point, refluxed for 3 hours, and the solvent was evaporated under reduced pressure to give 5.70 g (97.3%) of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one (III) as a deep orange solid. The compound thus obtained was pure enough as to be used in the subsequent reaction step with no prior purification or optionally crystallized from an organic solvent, preferably ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C:13]([CH2:23][NH:24]C(=O)C)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:3]=1.Cl>O1CCCC1.O>[NH2:24][CH2:23][C:13]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:12]2[C:28](=[O:30])[NH:29][C:10]3=[CH:9][CH:8]=[C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:31])[C:16](=[C:11]23)[O:15][CH2:14]1
Reactant: CC(=O)NCC1(c2ccccn2)COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3(CN)c1ccccn1
Temperature: 100 °C

Procedure:
N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL) and concentrated hydrochloric acid (200 μL, 6 mmol) in water (800 μL). The reaction was heated to 100° C. for 4 h and was then purified without workup by prep HPLC on a C-18 column eluting a water:acetonitrile gradient buffered at pH 2 with TFA to give 4-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as off white solid (0.0045 g, 40%). LCMS calculated for C20H20N5O3 (M+H)+: m/z=378.1. found: 378.1. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.68-8.58 (m, 1H), 8.20 (bs, 2H), 7.84 (td, J=7.8, 1.8 Hz, 1H), 7.48-7.37 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.73 (d, 1H), 4.41 (d, 1H), 4.12-3.97 (m, 1H), 3.75-3.58 (m, 1H), 2.18 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:13][C:12]1[O:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][C:20]([F:19])([F:32])[F:31])=[CH:3][CH:4]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2OC(F)(F)F)cc1

Procedure:
Compound (115) was prepared from compound (26) and (2-trifluoromethoxy-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.97 mins, m/z (ES−)=391 (M−H for C20H15F3O5).
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=4)=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr>C(O)(=O)C>[C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=4)=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(c2ccc(-n3ccnc3-c3ccccc3)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(-n3ccnc3-c3ccccc3)cc2)n[nH]1

Procedure:
Similarly, reaction of 4,5-dihydro-6-[4-(2-phenyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone with bromine in acetic acid as described in this Example gives 6-[4-(2-phenyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][N:2]([C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)[N:4]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.O>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)[N:4]=3)[CH:29]=2)[C:25]([CH3:30])=[N:26]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1nn(C)c2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine (Example 23) (389 mg, 0.92 mmol) in DMF (4 ml) was added Cs2CO3 (600 mg, 1.84 mmol) followed by iodomethane (64 ul, 1.02 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. Purification of crude product by prep TLC provided 260 mg of N4-(1,3-dimethyl-1H-indazol-6-yl)-N4-methyl-N2-{3-[(methylsulfonyl)methyl]-phenyl}-2,4-pyrimidinediamine. 1H NMR (300 MHz, d6DMSO) δ 9.25 (s, 1H), 7.86 (d, J=6.0 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 5.83 (d, J=6.0 Hz, 1H), 4.28 (s, 2H), 3.92 (s, 3H), 3.49 (s, 3H), 2.87 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 437 (M+H).