Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)C=CC=CC=1.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([OH:26])=[CH:23]2)=[CH:18][C:17]=1[Br:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([O:26][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:23]2)=[CH:18][C:17]=1[Br:27])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Oc1ccc2cc(Br)c(OCc3ccccc3)cc2c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCCCOc1ccc2cc(Br)c(OCc3ccccc3)cc2c1
Yield: 3 %

Procedure:
Following GENERAL METHOD 5-1 for phenol alkylation using 7-(benzyloxy)-6-bromonaphthalen-2-ol (506.5 mg, 1.54 mmol) and tert-butyl 3-bromopropylcarbamate (409 mg, 1.72 mmol) and after column chromatography (eluting with 3-80% EtOAc/heptane) tert-butyl (3-((7-(benzyloxy)-6-bromonaphthalen-2-yl)oxy)propyl)carbamate was obtained as an off-white solid (706 mg, 94% yield). MS (M-Boc)=388.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (s, 1H), 7.59 (d, J=9.60 Hz, 1H), 7.54 (d, J=8.08 Hz, 2H), 7.42 (t, J=7.58 Hz, 2H), 7.32-7.37 (m, 1H), 7.13 (s, 1H), 7.05-7.00 (m, 2H), 5.26 (s, 2H), 4.68 (br. s, 1H), 4.14 (t, J=6.06 Hz, 2H), 3.37 (q, J=6.40 Hz, 2H), 2.09-2.01 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:5]=12.C1COCC1>CO>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][OH:31])=[CH:32][CH:33]=3)[N:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[C:5]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(CO)cc1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
Sodium borohydride (19 mg, 0.491 mmol) was added to a solution of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (100 mg, 0.245 mmol) in methanol (2 mL). After 16 hours, THF (1 mL) and more sodium borohydride (19 mg, 0.491 mmol) was added. 5 hours later, the solvent was removed and water was added. The aqueous layer was extracted with dichloromathane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate/dichloromethane (80:20 to 100:0) as mobile phase to give {4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]phenyl}methanol (36 mg, 36%). 1H NMR (DMSO-d6) δ 4.56 (s, 2H), 5.27 (bs, 1H), 7.16 (m, 5H), 7.47 (m, 4H), 7.76 (d, J=8.64 Hz, 2H), 8.18 (d, J=8.52, 2H), 8.37 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ =410.1, Rt=2.43 min.
Reaction SMILES: [C:1]1(C)[CH:6]=CC=[CH:3][CH:2]=1.C(O[CH2:12][CH2:13][CH3:14])(=O)C.C[Sn](C)(C)C.C=C>[W](Cl)(Cl)(Cl)(Cl)(Cl)Cl.CO>[CH2:1]=[CH2:2].[CH2:12]=[CH:13][CH3:14].[CH2:6]=[CH:1][CH:2]=[CH2:3]
Reactant: CCCOC(C)=O
Reactant: Cc1ccccc1
Agent: Cl[W](Cl)(Cl)(Cl)(Cl)Cl
Agent: C=C
Agent: C[Sn](C)(C)C
Solvent: CO
Product: C=CC
Product: C=CC=C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Next, 5 g of the obtained polyolefin copolymer and 750 mL of dried toluene were charged into a 2000-mL SUS autoclave thoroughly purged with a nitrogen gas, and then, after the inner temperature of the autoclave was raised to 80° C., the mixture was agitated for 2 hours to dissolve the polyolefin copolymer. Thereafter, the inside of the polymerization vessel was pressurized to 0.8 MPa with ethylene. Then, a toluene solution containing 0.75 mmol of tungsten hexachloride, 7.5 mmol of propyl acetate, and 1.5 mmol of tetramethyl tin was charged into the autoclave, and the reaction was carried out for 60 minutes while maintaining the ethylene pressure at 0.8 MPa and the inner temperature at 80° C. Thereafter, 20 mL of methanol was added to terminate the reaction. After depressurized, the obtained reaction solution was passed through a column packed with 100 g of silica gel, and then the polymer was recovered from the reaction solution by precipitation in 4 L of methanol, and dried at 130° C. for 12 hours under vacuum. The yield of the obtained polyolefin polymer containing vinyl groups at both ends thereof was 3.9 g. In the composition of the polymer, the content of ethylene was 79.8% by mole, the content of propylene was 16.6% by mole, and the content of 1,3-butadiene was 3.6% by mole. The content of 1,3-butadiene contained 0.6% by mole of 1,4-addition structure, 0.5% by mole of 1,2-addition structure, 2.3% by mole of 5-membered ring structure, and 0.2% by mole of 3-membered ring structure. The terminal vinylation ratio of the polymer was 77%, and the intrinsic viscosity [η] was 0.12 dL/g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]#[CH:27])=[CH:21][CH:22]=3)[C:17]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[N:16][C:15]2=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1.C(OCC)(=O)C.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]#[CH:27])=[CH:21][CH:22]=3)[C:17]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[N:16][C:15]2=[S:47])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CCCc1ccc(OC)c(OC)c1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=S)n2CCCc1ccc(OC)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 130 mg (0.26 mmol) of the quinazolinone prepared in step D and 122 mg (0.30) mmol Lawesson reagent in 5 ml benzene is stirred for 2 h at 70° C. The solution turns slightly red. Equal amounts of Lawesson reagent are added after a total of 3 and 5 h, but the reaction remained incomplete. After extractive work-up with ethyl acetate and water, followed by chromatography of the crude material (hexane/ethyl acetate) the intermediate is obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:20][O:21]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl.O>[CH:20]([C:5]1[C:6]([OH:8])=[CH:7][C:2]([OH:1])=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:21]
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1c(C=O)c(O)cc(O)c1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
Compound 1 (0.25 g, 0.97 mmol) obtained in Example 1 was dissolved in dichloromethane (10 mL), and the solution was cooled to 4° C., and then dichloromethyl methyl ether (0.13 mL, 1.4 mmol) and tin(IV) chloride (0.17 g, 1.5 mmol) were added thereto and stirred at 4° C. for 5 minutes. Water (10 mL) and 3 mol/L hydrochloric acid (10 mL) were added to the reaction mixture, and extracted with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through preparative thin-layer chromatography (n-hexane/ethyl acetate=1/2) and crystallized (n-hexane/ethyl acetate=1/2) to obtain Compound 55 (0.21 g, 85%).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[N:35]1[CH:37]([C:41]([O:43][CH3:44])=[O:42])[CH2:38][CH2:39][CH2:40][CH:34]1[CH:33]2[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C1(CC2C3C(=C(OC)C=CC=3)N(C(CCC)C(OC)=O)C=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[N:35]1[CH:37]([C:41]([O:43][CH3:44])=[O:42])[CH2:38][CH2:39][CH2:40][C:34]1=[C:33]2[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)C1CCCC2C(Cc3ccccc3)c3cccc(OC)c3N12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC(C(=O)OC)n1cc(Cc2ccccc2)c2cccc(OC)c21
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCc2c(Cc3ccccc3)c3cccc(OC)c3n21

Procedure:
A solution of 1.8 gm (4.7 mmol) of the product from Part B and 4 mL (15 mmol) of tri-n-butyltin hydride in 5.0 mL of toluene was heated to reflux and treated dropwise with a solution of 85 mg (0.5 mmol) of 2,2′-azobis(2-methylpropionitrile). The solution was refluxed 1 hour after the addition, cooled, evaporated in vacuo, taken up in ethyl acetate, shaken with aqueous potassium floride, and filtered. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo to give a mixture of 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole and methyl 2-[3-phenylmethyl-7-methoxyindol-1-yl]pentanoate which was dissolved in 25 mL of dioxane and stirred with 450 mg (2 mmol) of dichlorodicyanoquinone for 30 minutes. The solution was evaporated in vacuo, taken up in dichloromethane, filtered through florisil, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/10-20% ethyl ether to give the title compound, 75 mg, 5%, as an amorphous solid. 1H NMR (CDCl3) δ: 1.70 (m, 1H), 1.85 (m, 1H), 2.20 (m, 1H), 2.35 (m, 1H), 2.70 (m, 1H), 3.00 (m, 1H), 3.70 (s, 3H), 3.80 (s, 3H), 4.00 (q, 2H), 5.65 (m, 1H), 6.50 (d, 1H), 6.90 (t, 1H), 7.00 (d, 1H), 7.10 (m, 1H), 7.20 (m, 4H).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[NH4+:5].[NH4+].S([O-])(O)=O.[NH4+].[S:12]([O:17]C)([O:15][CH3:16])(=[O:14])=[O:13]>>[CH3:16][S:1]([O-:4])(=[O:3])=[O:2].[NH4+:5].[S:12]([O-:17])([O-:15])(=[O:14])=[O:13].[NH4+:5].[NH4+:5]
Reactant: COS(=O)(=O)OC
Reactant: O=S([O-])[O-]
Agent: O=S([O-])O
Agent: [NH4+]
Product: CS(=O)(=O)[O-]
Product: O=S(=O)([O-])[O-]

Procedure:
WO 00/31027 discloses a process for oxidizing dimethyl disulfide with nitric acid to MSA, the oxides of nitrogen which are formed being reacted with O2 to give nitric acid again and this being recycled to the process. CN1 810 780 A discloses a process in which ammonium sulfite and/or ammonium hydrogen sulfite is reacted with dimethyl sulfate to give ammonium methanesulfonate and ammonium sulfate. The ammonium sulfate can be precipitated with Ca2+ as CaSO4. MSA can be liberated from the remaining Ca(CH3SO3)2 with sulfuric acid and can be worked up, once again CaSO4 being precipitated. EP 906 904 A2 discloses a process in which sodium sulfite is reacted with dimethyl sulfate. MSA can be liberated from the resulting mixture after acidification with concentrated sulfuric acid. The three last mentioned processes have the advantage that the MSA obtained is virtually free of chlorine compounds.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CCC(=O)c1cc2c(cc1O)CCCC2
Product: C=CCOc1cc2c(cc1C(=O)CC)CCCC2
Yield: 108.4 %

Procedure:
The product of step (b) (14.5 g) was treated with allyl bromide (11.5 g) under the conditions of Example 1(a) to give the title compound (18.8 g) as a pale brown oil, whose structure was confirmed by MS and NR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.ClCC(CCl)=O.[C:22]1([CH3:28])[CH:27]=CC=CC=1.[C:29]([O-:32])(=[O:31])[CH3:30].[Na+]>CO.CS(C)=O>[C:29]([O:32][CH2:28][C:22]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:27]=1)(=[O:31])[CH3:30]
Reactant: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: O=C(CCl)CCl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(=O)OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 51 %

Procedure:
(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (950 g, 4.42 mol) and 1,3-dichloroacetone (1045 g, 8.23 mol)were added to toluene (4.75 L) and the mixture was subjected to refluxing azeotropic dehydration using a Dean-Stark tube for 8 hours. During the reaction, an azeotropic mixture (2.38 L) was removed. The reaction mixture was concentrated under reduced pressure, and dimethyl sulfoxide (4.75L) and sodium acetate (905 g, 11.0 mol) were added to the residue. The mixture was stirred at 70-80° C. for 3.5 hours. Methanol (4.75 L) was added. After allowing to cool to room temperature and stirring, the mixture was stirred for 1 hour under ice-cooling. The precipitated crystals were collected by filtration, washed with cold-methanol (1.9 L), and dried under reduced pressure to give 4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (1560 g, yield 51%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][CH:17]2[CH2:19][CH2:18]2)=[C:4]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: NC1CC1
Reactant: O=Cc1ccc(Br)cc1Oc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ccc(CNC2CC2)c(Oc2cccnc2)c1
Reaction time: 18 h
Yield: 75.8 %

Procedure:
To a mixture of 4-bromo-2-(pyridin-3-yloxy)-benzaldehyde (2.0 g, 7.19 mmol) in DCE (75 mL) were added cyclopropylamine (0.50 mL, 7.2 mmol), acetic acid (2.16 mL, 36.0 mmol), and NaBH(OAc)3 (95%; 3.62 g, 18.0 mmol) portionwise. After 18 h, the mixture was diluted with 50 mL DCM and washed with 1 M NaOH (2×25 mL). The organic layer was dried (Na2SO4) and concentrated. FCC purification (EtOAc/DCM) gave the desired product (1.74 g, 76%). MS (ESI): mass calcd. for C15H15BrN2O, 318.04; m/z found, 319.1, 321.1 [M+H]+. 1H NMR (CDCl3): 8.42-8.39 (m, 2H), 7.31-7.26 (m, 4H), 7.00-6.99 (m, 1H), 3.84 (s, 2H), 2.11-2.07 (m, 1H), 0.43-0.40 (m, 2H), 0.36-0.33 (m, 2H).
Reaction SMILES: [O:1]([CH2:5][CH3:6])[C:2]([S-:4])=[S:3].[K+].O.[CH2:9]([S:11][CH:12]1[N:15]([CH:16](Cl)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:31])[CH2:13]1)[CH3:10]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH2:9]([S:11][CH:12]1[N:15]([CH:16]([S:3][C:2]([O:1][CH2:5][CH3:6])=[S:4])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C:14](=[O:31])[CH2:13]1)[CH3:10]
Reactant: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=S)[S-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=S)SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reaction time: 1 h

Procedure:
To a stirred mixture of 3.2 g. of potassium ethyl xanthate, 5.4 g. of benzyltriethylammonium chloride, 100 ml. of water and 50 ml. of dichloromethane, at 0° C., was added a solution of 7.12 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-chloroacetate in 75 ml. of dichloromethane. Stirring was continued at 0°-5° C. for 1 hour, and then the organic phase was removed. The aqueous phase was extracted with 100 ml. of dichloromethane, and then the combined dichloromethane layers were washed successively with 75 ml. of dilute hydrochloric acid, 75 ml. of saturated aqueous sodium bicarbonate and 75 ml. of water. The dichloromethane solution was dried with anhydrous sodium sulfate and evaporated to dryness in vacuo, and the residue was purified by column chromatography on 200 g. of silica gel, eluting with 95:5 chloroform-ethyl acetate. The product containing fractions were combined and concentrated in vacuo to give 4.3 g of the title compound. The IR spectrum (chloroform) showed an absorption at 5.66 microns. The NMR spectrum (deuterochloroform) showed peaks at 1.02-1.6 (m, 6H); 2.35-3.65 (m, 4H); 4.4-5.1 (m, 3H); 5.3 (s, 2H); 6.3 and 6.4 (ss, 1H); 7.4 (d, 2H); and 8.2 (d, 2H) ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][N:14]1[C:22]2[CH:21]=[C:20]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])[CH:19]=[CH:18][C:17]=2[C:16]2[CH2:40][NH:41][CH2:42][CH2:43][CH2:44][C:15]1=2>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:42][CH2:43][CH2:44][C:15]2[N:14]([CH3:13])[C:22]3[CH:21]=[C:20]([N:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=5)=[CH:25][C:24]4=[O:39])[CH:19]=[CH:18][C:17]=3[C:16]=2[CH2:40]1)(=[O:10])[CH3:9]
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Triethylamine (58 μL, 0.41 mmol), DMAP (5.0 mg, 0.041 mmol) and acetyl chloride (22 μL, 0.31 mmol) were added to a solution of 1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride (97 mg, 0.21 mmol) in CH2Cl2 (15 mL), and the resulting solution was stirred at ambient temperature for 18 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 1 column volume, then increased to 0:100 over 10 column volumes and held for 12 column volumes) gave the title compound (58 mg, 59%) as a yellow powder: mp 156-162° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.72-7.49 (m, 2H), 7.07-6.99 (m, 2H), 6.80-6.78 (m, 1H), 4.72-4.70 (m, 2H), 3.79-3.76 (m, 2H), 3.69-3.68 (m, 3H), 3.05-2.98 (m, 2H), 2.02-1.90 (m, 5H); ESI MS m/z 481 [M+H]+; HPLC (Method A)>99% (AUC), tR=18.1 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]2=[O:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:23].BrBr>O>[Br:23][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[C:15](=[O:22])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20]
Reactant: Br
Reactant: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Agent: BrBr
Solvent: O
Product: O=C1NC(=O)C(Br)(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4′-phenoxyphenyl)barbituric Acid (48 mg) in 0.23 ml of water, cooled at 0° C. and under stirring, are added 23 ml of 48% hydrobromic acid and successively 9 μl of bromine. After 2 hours at room temperature additional 9 μl of bromine are added and stirring is continued for 2 hours. The suspended solid is then filtered and washed with water, to give, after drying under vacuum at 60° C., 57 mg of the product, m.p. 125-127° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[I:18][CH2:19][CH2:20][OH:21]>C1COCC1>[I-:18].[OH:21][CH2:20][CH2:19][N+:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1
Reactant: OCCI
Reactant: CN1CCCN(c2nc3ccccc3o2)CC1
Solvent: C1CCOC1
Product: C[N+]1(CCO)CCCN(c2nc3ccccc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
A 100 mg portion of 2-(4-methyl-1-homopiperazinyl)-benzoxazole was dissolved in 3 ml of THF. Under cooling with ice, 89 mg of 2-iodoethyl alcohol was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 29 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and 3 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 143 mg of the title compound.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>CN(C)C(=O)C>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: FC(F)CNCc1ccccc1
Yield: 90.2 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 18.7 g of N,N-dimethylacetamide in an autoclave at an internal temperature of 120° C. for 6 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 30 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 7.1 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 90%, based on benzylamine
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]=1[NH2:23])(C)(C)C.CC1(C)O[C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=[O:40])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:30]([C:32]3[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=3)[C:35]#[N:36])[CH2:29][C:28](=[O:40])[NH:23][C:9]=2[CH:10]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COc1cccc(F)c1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(F)c1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from (3-amino-2′-fluoro-6′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G44) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white solid (47 mg).