Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([NH2:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:16])[CH3:15]
Reactant: NC(=O)c1ccccc1
Reactant: CC(=O)c1cccc(-c2ccnc(Cl)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)c1cccc(-c2ccnc(NC(=O)c3ccccc3)c2)c1
Yield: 54.9 %

Procedure:
A degassed mixture of 1-[3-(2-Chloro-pyridin-4-yl)-phenyl]-ethanone (500 mg, 2.16 mmol), benzamide (523 mg, 4.32 mmol, 2 eq.), Xantphos (120 mg, 0.21 mmol, 0.1 eq.), Pd(OAc)2 (24 mg, 0.10 mmol, 0.05 eq.), K2CO3 (448 mg, 3.24 mmol, 1.5 eq.) in dioxane (12 mL) was irradiated with microwaves at 150° C. for 1 hour. LC/MS control. Conversion was mostly 100% based on disappearance of starting material. Dimer (M+: 392) being the major by-product. If any starting material is unreacted at this point, another portion of Xantphos and Pd(OAc)2 may be added and the mixture microwaved for another 30 minutes. The mixture was then partitioned between DCM and water (20 mL/10 mL). The layers were separated and the aqueous layer was washed further with DCM (2×20 mL). The combined organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was chromatographed using 1/1 Hexane/EtOAc to give N-[4-(3-Acetyl-phenyl)-pyridin-2-yl]-benzamide as a white solid (375 mg, 55%). MS: m/z 317.1 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCl
Yield: 56.2 %

Procedure:
A suspension of 4-chloro-6-methoxyquinazolin-7-ol (1.2 g, 5.8 mmol), 1 bromo 2 chloroethane (5.69 ml, 6.8 mmol), potassium carbonate (2.36 g, 17.4 mmol) and dimethylformamide (15 ml) were heated to 90 C for 1.5 hours. The excess potassium carbonate was filtered off and the reaction evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 60-100% dichlormethane in hexane and 30-50% ethyl acetate in hexane to give 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline as a solid (0.89 g, 57%). NMR Spectrum: (CDCl3) 3.98 (t, 2H), 4.08 (s, 3H), 4.47 (t, 2H), 7.36 (s, 1H), 7.42 (s, 1H), 8.87 (s, 1H). Mass Spectrum: M+H+ 273.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C(OC(C)(C)C)(=O)[NH:18][NH2:19].FC(F)(F)C(O)=O>ClCCl.O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][NH2:19])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of 3-iodobenzoic acid (1.24 g, 5.0 mmol) in 15 mL of dichloromethane containing one drop of N,N-dimethylformamide was treated dropwise with oxalyl chloride (0.70 mL, 7.5 mmol). After stirring for 2.5 h at room temperature, the solution was concentrated under reduced pressure to afford a pale orange oil, which was dissolved in 10 mL of dry tetrahydrofuran (THF) and added dropwise to an ice-cold suspension of tert-butyl carbazate (793 mg, 6.0 mmol) and triethylamine (1.10 mL) in 15 mL of dry THF. The resultant mixture was allowed to warm to room temperature overnight, and was then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was washed sequentially with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure to afford an off-white solid. Trituration with hexanes afforded a white powder, which was suspended in 60 mL of dichloromethane and cooled in an ice-water bath. Trifluoroacetic acid (25 mL) was added dropwise, and the mixture was warmed to room temperature. After 1 h, the solution was concentrated under reduced pressure, and the residue was dissolved in 60 mL of water and was neutralized to pH 8 with 1N aqueous sodium hydroxide solution. The resultant precipitate was collected, washed with water, and dried in vacuo to afford 3-iodobenzhydrazide as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[N:6][NH:7][C:8]2=[O:15])#[CH:2].Cl.BrC1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(NCC)C.O.[Cu]I>[CH3:14][O:13][C:12]1[C:3]([CH2:1][C:2]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][N:6]=[CH:5]2
Reactant: Brc1ccncc1
Reactant: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1Cc1ccncc1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
A suspension of 5-ethynyl-6-methoxy-2H-phthalazin-1-one (1.9 g, 9.49 mmoles), prepared as described in example 140, 4-bromopyridine hydrochloride (2.214 g, 11.39 mmoles), bis(triphenylphosphine)PdCl2 (133 mg, 0.1998 mmole) and CuI (36 mg, 0.1898 mmole) in diethylamine (40 ml) was heated at 75° C. for 1 hour, cooled, diluted with water (40 ml) and the solid was filtered after 30 minutes under stirring. The solid was suspended in acetone, stirred for 15 minutes, filtered again and dried in oven at 45° C. under vacuum giving 2.263 g of the title compound (yield: 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:29]([OH:31])=O)[CH2:13][C:14]1[N:18]=[CH:17][N:16](C(OCC2C=CC=CC=2)=O)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:29]([N:41]1[CH2:42][CH2:43][N:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:39][CH2:40]1)=[O:31])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(N[C@@H](Cc1cn(C(=O)OCc2ccccc2)cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCN(c2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
7.13 g of N,N'-dibenzyloxycarbonyl histidine, 3.00 g of 4-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were dissolved in 100 ml of tetrahydrofuran, and to the mixture was added 3.84 g of DCC (dicyclohexylcarbodiimide), and the whole was stirred at a room temperature for three hours. An insoluble matter was filtered off, the filtrate was concentrated under a reduced pressure, and to the concentrate was added 200 ml of ethyl acetate to reform crystals, which were then filtered off. The filtrate was sequentially washed with 20% potassium carbonate aqueous solution and saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting residue was dissolved in 60 ml of methanol, and after an addition of a 10% ammonium-methanol solution and stirring at a room temperature for 30 minutes, the solution was concentrated under a reduced pressure to obtain a residue, which was then subjected to silica gel chromatography and eluted with chloroform/methanol (50:1 to 10:1) to obtain 6.61 g of the title compound in a colorless amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([OH:21])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:21]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 0.54 g, 2.8 mmol) and 3-bromo-5-trifluoromethyl benzoic acid (0.81 g, 3.0 mmol) in DMF (7 mL) were added TBTU (0.96 g, 3.0 mmol) and DIPEA (1.41 g, 10.9 mmol). The reaction mixture was stirred under nitrogen overnight at RT and then partitioned between ethyl acetate and an aqueous NaHCO3 solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic solutions were washed twice with water and then dried by a phase separator column. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (ethyl acetate-heptane 10% to 17%). There was obtained 0.86 g (68%) of 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide. 1H NMR (500 MHz, CDCl3): 2.1-3.8 (cm, 8H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.8-7.4 (cm, 6H), 7.8 (s, 1H). LCMS: m/z 445 (M+1)+.
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25]C(=O)C)=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:31][CH2:32][C:33]1[O:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:31][CH2:32][C:33]1[O:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccco2)c1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccco2)c1Oc1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 3 g of 4-phenoxy-3-furfurylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid and 30 ml of 2N aqueous sodium hydroxide is refluxed for 4 1/2 hours. After cooling to room temperature it is acidified with hydrochloric acid to pH = 2. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-phenoxy-3-furfurylamino-5-(2-aminophenylsulfamoyl)-benzoic acid melting at 105°-110° with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 71 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol), using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone, was converted to the title compound (100 mg, 71%) which was obtained as a yellow solid. MS: m/e=417.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[S:21][C:20]=1[C:19]([O:18][CH2:16][CH3:17])=[O:22]
Reactant: N#Cc1nccnc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2nccnc2c1N
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A mixture of 3-chloropyrazine-2-carbonitrile (17.9 g, 128 mmol), sodium carbonate (17.7 g, 167 mmol) and ethyl-2-mercaptoacetate (18.4 mL, 167 mmol) in ethanol (120 mL) was heated to reflux for 4.5 h. Quenched with water (1.5 L) and stirred for 30 min. The resulting precipitate was collected and washed with water. The residue was dissolved in diethyl ether and a black precipitate was filtrated off. Ether was evaporated to give pure compound ethyl 7-aminothieno[2,3-b]pyrazine-6-carboxylate 7 (19.6 g, 68.5%). 1H-NMR (400 MHz, CDCl3) 1.42 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 6.19 (br s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ncc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 40.5 %

Procedure:
Using (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 229 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (80 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[F:35][C:34]([F:36])([F:37])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a stirred mixture of N-(4-(piperidine-4-carbonyl)phenyl)acetamide (3.82 mmol, 0.94 g) and potassium carbonate (11.45 mmol, 1.582 g) in N-methyl-2-pyrrolidinone (5 mL) was added 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.82 mmol, 1.286 g). The reaction was stirred at room temperature over the weekend. Methanol (30 mL) was added and the reaction was filtered. The filtrate was purified by strong cation exchange column chromatography to afford the title compound (1.51 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl>>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: Fc1ccccc1CCl
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccccc1CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g; 0.010 mole in 75 ml DMF) and 10 g milled K2CO3 was added 2-fluorobenzyl chloride (3.18 g; 0.022 mole in 15 ml DMF). This was stirred at 85° C. for 1.5 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[C:24](=[O:25])[NH:23][CH:22]=[CH:21][C:15]=3[N:16]=[C:17]([S:19][CH3:20])[N:18]=2)=[CH:8][CH:7]=1.[Br:29]N1C(=O)CCC1=O>CN(C=O)C>[Br:29][C:21]1[C:15]2[N:16]=[C:17]([S:19][CH3:20])[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[CH:3]=4)=[CH:11][CH:10]=3)[C:14]=2[C:24](=[O:25])[NH:23][CH:22]=1
Reactant: CSc1nc(Nc2ccc(Oc3cccc(F)c3)cc2)c2c(=O)[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CSc1nc(Nc2ccc(Oc3cccc(F)c3)cc2)c2c(=O)[nH]cc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A 40 mL reaction vial was charged with 238d, (1.00 g, 2.53 mmol) in 15 mL of DMF. The mixture was gently heated until it became a clear solution, and allowed to cool down to room temperature. To the mixture was added N-bromosuccinimide (NBS, 498 mg, 2.80 mmol) and stirred for 1 h at rt. The solvent was removed under reduced pressure yielding the orange solid. The resulting solids were collected by filtration and washed acetonitrile to provide 1.04 g (87%) of the desired product 238e.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCNCC4)c3)oc12
Yield: 21.3 %

Procedure:
2-(3-(Pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (110 mg, 0.35 mmol) and platinum (IV) oxide monohydrate in methanol was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichloromethane:methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid. 24 mg 2-(3-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 21%. 1HNMR (400 MHz, DMSO-d6): δ 1.96 (m, 5H), 3.03 (m, 4H), 7.51 (m, 2H), 7.62 (t, 1H), 7.81 (d, J=6.4 Hz, 1H), 7.83 (brs, 1H), 7.94 (brs, 1H), 7.97 (d, J=6.4 Hz, 1H), 8.14 (s, 1H), 8.19 (d, J=6.4 Hz, 1H), 8.85 (brs, 1H), 9.02 (brs, 1H). LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC[O:29][S:30]([CH3:33])(=O)=[O:31])=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][OH:75])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:76])[CH:37]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][S:30]([CH3:33])(=[O:31])=[O:29])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:76])[CH:37]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCO
Reactant: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]

Procedure:
Compound 32c was prepared as described hereinabove for Compound 32a, using Compound 29c (0.067 gram, 0.1 mmol), methanesulfonyl chloride (0.036 gram, 0.32 mmol) and triethylamine (0.053 gram, 0.53 mmol) in dichloromethane (6.7 ml), yielding 0.02 gram of the product (26% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]4[CH:48]=[CH:47][C:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[CH:33][CH:32]=4)[CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].C1(C)C=CC=CC=1>C(Cl)Cl>[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:47][CH:48]=4)[CH2:27][CH2:28]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)O)cc4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoate [Example 1, step d] (0.55 g) in DCM (20 mL) and the resultant solution allowed to stand at 20° C. for 1 hour. Toluene (30 mL) was added and the solvents were evaporated under reduced pressure. The residue was azeotroped with acetonitrile (×2) to yield the subtitled compound. Yield 0.60 g.
Reaction SMILES: CN(C)CCO[C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl:23]C1C2C(=O)C3C(=CC=CC=3)NC=2C=CC=1.ClC1C=C(NC2C=CC=CC=2C(O)=O)C=CC=1.S(=O)(=O)(O)O>C(O)C>[Cl:23][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c2ccccc2[nH]c2cccc(Cl)c12
Reactant: CN(C)CCOc1cccc2c1c(=O)c1ccccc1n2C
Agent: O=C(O)c1ccccc1Nc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1c2ccccc2c(=O)c2c(Cl)cccc21

Procedure:
1-(2-dimethylaminoethoxy)-10-methyl-9(10H)-acridinone [IV; R' is CH3, R" is H, --O--Y--N=Z is 1--O--CH2CH2N(CH3)2 ], hydrochloride salt, m.p. 237°-241° C. (tan granules from methanol-ether). The intermediate 1-chloro-10-methyl-9(10H)-acridinone, m.p. 183°-186° C. (pale yellow granules from ethanol) was prepared by N-methylation of 1-chloro-9(10H)-acridinone, in turn prepared by cyclization of 2-(m-chlorophenylamino)benzoic acid with sulfuric acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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:14]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2ncnc(Cl)c2c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2ncnc(-c3ccccc3)c2c1

Procedure:
4-Chloro-quinazoline-6-carbaldehyde (50 mg, 0.26 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol), phenylboronic acid (63 mg, 0.52 mmol) and sodium carbonate (sat. sol: 50 ul) were heated up in toluene at 100° C. for 12 h. After evaporation of the solvents, the residue was taken up in ethyl acetate and washed with brine twice. Organic phases were then concentrated and raw materiel was purified on silica gel using DCM/EtOH 95:5 as eluents to give 50 mgs (82%) of the desired cpd with a 85% purity.