Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[N:28]=[C:27]([NH:29][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H]1CCCN1c1cccc(N)n1
Reactant: Brc1cc(-c2ccccc2)nn2ccnc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccccc3)nn3ccnc23)n1
Temperature: 100 °C
Yield: 25 %

Procedure:
A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (0.15 g, 0.55 mmol), (S)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (0.107 g, 0.61 mmol), Pd2(dba)3 (32 mg, 0.055 mmol), BINAP (68 mg, 0.11 mmol) and Cs2CO3 (0.54 g, 1.65 mmol) in dioxane (20 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated and the residue purified by chromatography (silica gel, 20 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford (S)—N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (51 mg, 25%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.83 (s, 1H), 7.99 (s, 1H), 7.95-7.91 (m, 2H), 7.59 (s, 1H), 7.51-7.40 (m, 4 h), 6.29 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.28-4.24 (m, 1H), 3.64-3.60 (m, 1H), 3.48-3.40 (m, 1H), 2.18-2.10 (m, 3H), 1.78-1.75 (m, 1H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 371, tR=2.015 min, HPLC: 99.09% at 214 nm, 99.69% at 254 nm, tR=4.691 min.
Reaction SMILES: [N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:26](O)[CH3:27]>>[CH2:26]([O:18][C:17](=[O:19])[CH2:16][C:14]1[CH:13]=[CH:12][C:9]2[O:10][C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH3:27]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc2c(c1)CCc1cccnc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a mixture of 20 mg of (5,6-dihydro benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetic acid and 0.5 ml of ethanol was added 2.5 ml of a saturated hydrogen chloride gas-ethanol solution, and the resulting mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, this was basified with a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an oil, which was chromatographed over 1 g of silica gel and eluted with benzene/chloroform (9/1-8/1), thereby yielding 18 mg (yield: 81.8%) of ethyl(5,6-dihydro benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetate as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=C([N+]([O-])=O)C=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:27]([O-])=O.C(O)C.O.NN.[H][H]>[Ni].O>[NH2:27][C:3]1[CH:4]=[C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C(C(F)(F)F)C(F)(F)F)ccc1O

Procedure:
30 parts by weight 2,2-bis (4-hydroxy-3-nitrophenyl)-1,1,1,3,3,3-hexafluoropropane are suspended in a mixture of 240 parts by weight ethanol and 120 parts by weight water. 1.5 parts by weight Raney nickel and two times 18.5 parts by weight hydrazine hydrate are added to the suspension, and subsequently, the mixture is heated for the reflux. After the development of hydrogen has abated at the end of about 4 hours, suction is applied to remove the Raney nickel and the ethanol/water mixture is removed in a vacuum. The residue is taken up with about 400 parts by weight of diluted hydrochloric acid and optionally filtered off from insoluble components. After the addition of sodium acetate and sodium carbonate, the 2,2-bis (3-amino-4- hydroxy phenyl)-1,1,1,3,3,3-hexafluoropropane is precipitated; the yield is approximately 66%. Analysis (reported/found) revealed the following data: C 49.2%/49.0%; H 3.3%/3.4%; N 7.7%/7.5%; F 31.1%/31.0%; 1H-NMR in d6 -DMSO: δ (ppm)=9.2 (2H,s,OH), 6.6 (6H, m,aromatic), 4.6 (4 H, s, --NH2).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Sn:20](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[S:11][C:12]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][N:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(CO[Si](C)(C)C(C)(C)C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
2-((tert-butyldimethylsilyloxy)methyl)thiazole (8.0 g, 35 mmol) was dissolved in dry THF (350 mL) and the solution was cooled to −78° C. To this solution, t-BuLi (1.7 M, 25 mL, 42 mmol) was added dropwise. The reaction was warmed to −40° C. and stirred for 2 hours. Then, Bu3SnCl (14.6 g, 45 mmol) was added and the resulting mixture was allowed to warm to room temperature slowly and stirred for another 30 min. NH4Cl (aq.) was added to quench the reaction and extracted with EtOAc. The organics was dried and concentrated. The residue was purified with column (silica gel, 0˜30 EtOAc/hexane) to give the product 2-((tert-butyldimethylsilyloxy)methyl)-5-(tributylstannyl)thiazole (14.1 g)
Reaction SMILES: [F-].[K+].FC(F)(F)C(C(F)(F)[C:14]([F:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])(C(F)(F)F)C([O-])=O.FC(F)(F)C(F)=C(F)F.[F:37][C:38]([C:46]([F:49])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[C:39](F)=[O:40]>COCCOCCOC>[F:16][C:15]([F:18])([F:17])[C:14]([F:23])([C:19]([F:22])([F:21])[F:20])[C:39](=[O:40])[C:38]([F:37])([C:46]([F:49])([F:48])[F:47])[C:42]([F:45])([F:44])[F:43]
Reactant: O=C([O-])C(C(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Agent: FC(F)=C(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Yield: 95.2 %

Procedure:
8.1 g (0.14 mol) of anhydrous potassium fluoride, 216 g (0.50 mol) of perfluoro(isobutyl isobutyrate) and 200 g of anhydrous diglyme were charged to a clean dry 600 mL Parr pressure reactor. After cooling the reactor to <0° C., 165 g (1.10 mol) of hexafluoropropylene was added to the resulting mixture. The contents in the reactor were allowed to react overnight at 70° C. with stirring, then the reactor was allowed to cool and the excess pressure in the reactor was vented to the atmosphere. The contents of the reactor were then phase split to obtain 362.5 g of lower phase. The lower phase was retained and mixed with lower phases saved from previous analogous reactions. To 604 g of accumulated lower phases containing 22% perfluoroisobutyryl fluoride and 197 g (1.31 mol) of hexafluoropropylene was added 8 g (0.1 mol) of anhydrous potassium fluoride and 50 g of anhydrous diglyme, and the resulting mixture was allowed to react in the Parr reactor in the same manner as before. This time 847 g of lower phase resulted, containing 54.4% desired material and only 5.7% perfluoroisobutyryl fluoride. The lower phase was then water washed, dried with anhydrous magnesium sulfate, and fractionally distilled to give 359 g of 1,1,1,2,4,5,5,5-octafluoro-2,4-bis(trifluoromethyl)pentan-3-one having 95.2% purity as determined by gas chromatography and mass spectroscopy (“gcms”) (47% theoretical yield) and having a boiling point of 73° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C)CCN1c1nccc(N)n1
Temperature: 220 °C
Yield: 18.4 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), Hunig's base (809 μl, 4.63 mmol) and (3R)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (650 mg, 3.47 mmol) in N,N-dimethylformamide (DMF) (3 ml) was heated in a microwave reactor at 220° C. for 60 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 18% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N1CCCCC1.[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26]([CH:27]=O)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH:19]=2)[CH2:16][CH2:15]1>C(O)C.O>[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26](/[CH:27]=[C:7]4/[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]/4)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[CH:19]=2)[CH2:16][CH2:15]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(F)c3)nc12
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cccc(F)c4)nc23)N1
Temperature: 80 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
Hydantoin (69 mg, 0.69 mmol) and piperidine (69 μL, 0.69 mmol) were added to 7-(cyclopropylamino)-5-(3-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (72 mg, 0.23 mmol) dissolved in ethanol (1.1 mL). The reaction was heated at 80° C. After 15 h, the reaction was cooled to r.t., diluted with water (5 mL), and the precipitate was collected and washed with 1:1 ethanol:water (5 mL). The bright yellow solid was dried in vacuo to give (Z)-5-((7-(cyclopropylamino)-5-(3-fluorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (25 mg, 10% over 3 steps). LCMS (M+1=507)
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>CCCCCC.CCOCC>[OH:17][C:11]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2nccs2)CCCCC1
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of n-BuLi (22 mL of a 2.5M solution in hexane, 55 mmol) in anhydrous ether (60 mL) at −78° C. was slowly added a solution of thiazole (3.94 g, 46 mmol) in anhydrous ether (30 mL). The resulting mixture was stirred for 1 h and then cyclohexanone (9.6 mL, 93 mmol) in ether (25 mL) was added over 5 min. The mixture was stirred for 2.5 h at −78° C. and then sat. aq. NH4Cl was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided the 2-[(1-Hydroxy)cyclohexyl]thiazole compound (5.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:33])([F:32])[F:31])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=1)=[O:29]
Reactant: O=C(c1ccccc1[N+](=O)[O-])c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Fe (176 mg, 3.15 mmol) in glacial acetic acid (5 mL) was added a solution 4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (410 mg, 0.788 mmol) in AcOH (5 mL) at 80° C. for 15 minutes. After complete addition the mixture was stirred at the same temperature for 30 minutes and the progress of the reaction was followed by LCMS. The reaction mixture was then cooled to room temperature and it was then diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and residue was portioned between NaHCO3 and EtOAc. The organic portion was separated and the aqueous portion was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1 H), 8.42 (d, J=2.4 Hz, 1 H), 8.12 (d, J=2.0 Hz, 1 H), 7.93 (d, J=2.4 Hz, 1 H), 7.64-7.61 (m, 1 H), 7.30-7.26 (m, 2 H), 7.03-7.00 (m, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 6.47-6.43 (m, 1 H), 6.26 (s, 2 H); Mass spectrum m/z: 490.0 (M+H).
Reaction SMILES: [Br-:1].[CH3:2][N:3]([CH3:39])[C:4]1[CH:5]=[CH:6][C:7]2[C:16]([CH:17]=1)=[O+:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([N:18]([CH3:20])[CH3:19])[CH:13]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([NH2:30])[C:22]=1[C:31]([O:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:32]>C(O)C.ClCCl.[Pd]>[Br-:1].[CH3:20][N:18]([CH3:19])[C:12]1[CH:11]=[CH:10][C:9]2[C:14]([CH:13]=1)=[O+:15][C:16]1[C:7](=[CH:6][CH:5]=[C:4]([N:3]([CH3:2])[CH3:39])[CH:17]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:30])[C:22]=1[C:31]([O:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:32]
Reactant: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc([N+](=O)[O-])c1N
Agent: [Pd]
Agent: [Br-]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc(N)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
The aforementioned 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3-amino-4-nitrophenyl)xanthylium bromide (443 mg) was dissolved in a mixed solvent of ethanol (100 ml) and dichloromethane (100 ml), and the solution was added with 0.25 g of 10% Pd/C catalyst. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3,4-diaminophenyl)xanthylium bromide (214 mg, 50.9%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][CH:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.8 %

Procedure:
4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (20 mg, 0.046 mmol, 1 eq), DIPEA (16 μl, 0.091 mmol, 2 eq) and TBTU (16 mg, 0.05 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 3-aminoquinuclidine dihydrochloride (11 mg, 0.055 mmol, 1.1 eq). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide (±)-4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide (8 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[CH:15](I)([CH3:17])[CH3:16]>C1COCC1.C([Li])(C)(C)C.O>[CH:15]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)([CH3:17])[CH3:16]
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CC(C)I
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
To a cooled solution (−78° C.) of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.00 g, 9.51 mmol) in THF (35 mL), tert.-butyllithium (16 mL, 1.5 M solution in pentane) is added. The mixture is stirred at −78° C. for 10 min before isopropyliodide (7.60 g, 48.7 mmol) is added. The reaction mixture is stirred at −78° C. for 3 h, then at rt for 3 d. The reaction mixture is diluted with water and extracted twice with EA. The combined organic extracts are dried over Na2SO4 and evaporated. The crude product is purified by CC on silica gel eluting with DCM/TBME 20:1 followed by prep. HPLC to give 3-isopropyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (500 mg) as a white solid; LC-MS: tR=1.04 min, [M+1+CH3CN]=294.16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH2:18]([O:20]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:19].[Cl-].[Li+]>C1COCC1.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:18]([C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1)(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(Br)cn1-c1ncccc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)cn1-c1ncccc1Cl

Procedure:
Under argon, 5.0 g (15.6 mmol) of methyl 4-bromo-1-(3-chloropyridin-2-yl)-1H-pyrrole-2-carboxylate were dissolved in THF, and 8.2 g (21.9 mmol) of (1-ethoxyvinyl)tributylstannane, 2.1 g of lithium chloride and 0.9 g (0.8 mmol) of tetrakis(triphenylphosphine)palladium were added at room temperature and the mixture was stirred under reflux for 48 h. The solvent was then distilled off, and the residue was taken up in 200 ml of THF and stirred in the presence of 12 ml of 2N hydrochloric acid at RT for a further 24 h. Once more, the solvent was distilled off, and the residue was dissolved in 120 ml of methyl tert-butyl ether and, at RT, stirred vigorously with 120 ml of saturated potassium fluoride solution for 1 h. The organic phase was separated off and concentrated. The desired product was isolated by chromatographic purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CN=C1.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:16]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:12]
Reactant: OCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Compound 7-a, 4-chloro-1-butanol, (CAS 928-51-8) (100 g, 920 mmol) was dissolved in CH2Cl2 (1000 mL) at room temperature. Imidazole (CAS 288-32-4) (81.5, 1200 mmol) and TBDMS-Cl (CAS 18162-48-6) (152 g, 1010 mmol) was added at 0° C. The mixture was stirred for 4 h at rt. The mixture was filtered off. The filtrate was washed with 10% aqueous HCl-solution and brine. After evaporation of the filtrate, we get the product 7-c as a clear oil (100 g, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:31][CH2:32][N:33]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:36]([CH3:44])([CH3:43])[O:35][C:34]2=[O:45])[CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:27][C:28]2([CH2:31][CH2:32][N:33]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[C:36]([CH3:43])([CH3:44])[O:35][C:34]3=[O:45])[CH2:30][CH2:29]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC1(C)OC(=O)N(CCC2(N)CC2)c2ccccc21
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(OCc4ccccc4)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
Prepared from 900 mg (2.5 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 700 mg (2.7 mmol) of 1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one analogously to the method described for Example 16a. White solid. Yield: 630 mg (45%); mass spectroscopy: [M+H]+=558.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[CH:25]=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-2:27].[O-2:28].[O-2].[Cr+6:30].[S:31](=[O:35])(=[O:34])([OH:33])[OH:32]>CC(C)=O.O>[O-2:14].[O-2:32].[O-2:27].[Cr+6:30].[S:31](=[O:33])(=[O:32])([OH:35])[OH:34].[C:19]1([C:18]#[C:17][C:15]2[CH:16]=[C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:10]([C:25]([OH:27])=[O:26])=[CH:11][C:12]=2[C:13]([OH:28])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(C=O)c(C#Cc2ccccc2)cc1C#Cc1ccccc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(C(=O)O)c(C#Cc2ccccc2)cc1C#Cc1ccccc1
Temperature: 0 °C
Yield: 85.5 %

Procedure:
4,6-Bis(phenylethynyl)isophthalaldehyde (7.8 g, 0.023 mole) was dissolved in acetone (distilled from solid potassium permanganate) and the solution was chilled to 0° C. A chromium trioxide-sulfuric acid solution was prepared by slurrying 26.7 g of chromium trioxide in 23 ml of concentrated sulfuric acid and 40 ml of distilled water. This solution was diluted in the cold with distilled water to 110 ml. A portion of this solution (16.9 ml) was added dropwise over 1.5 hours to the stirred yellow acetone solution. During this period the color of the reaction mixture changed from yellow to brown and finally to green. After an additional 20 hours of reaction, the mixture was warmed to room temperature and poured into a vessel containing ice and water. The yellow precipitate was collected by filtration and washed thoroughly with water. Suction drying on the frit yielded 7.3 g (85.5% yield) of the light yellow 4,6-bis(phenylethynyl)-isophthalic acid.