Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:7][C@@H:6]2[CH2:8][C:3]1([C:9]([OH:11])=[O:10])[CH2:4][CH2:5]2>[Zn].C(O)(=O)C>[C:3]12([C:9]([OH:11])=[O:10])[CH2:8][CH:6]([CH2:5][CH2:4]1)[CH2:7][CH2:2]2
Reactant: O=C(O)C12CC[C@H](CC1Br)C2
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)C12CCC(CC1)C2
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A 2-L reactor equipped with an overhead mechanical stirrer, condenser, nitrogen gas inlet port, temperature probe and reagent charging port, was placed under an atmosphere of nitrogen. The reactor was charged with zinc powder (<10 micron) (298 g, 4560 mmol) and acetic acid (500 mL). While vigorously stirring the heterogeneous mixture, (4S)-2-bromobicyclo[2.2.1]heptane-1-carboxylic acid (100 g, 456 mmol) was then added. A second portion of acetic acid (500 mL) was then used to rinse the walls of the reactor. The reaction mixture was brought to a gentle reflux (ca. 30 min) and then held at this temperature for 5 h. The cooled (room temperature) reaction mixture was passed through a pad of Celite, which was washed with acetic acid (1×300 mL) and ethyl acetate (1 (500 mL). The filtrate was concentrated, water (300 mL) was added, and then the mixture was stirred vigorously to induce precipitation. The precipitate was collected by filtration, washed with water, and dried under vacuum at 35° C. overnight. Pentane (50 mL) was then added, and the mixture was stirred vigorously for 20 min during which time a fine white precipitate formed. The resulting precipitate was filtered, washed with pentane (20 mL), and air dried to afford bicyclo[2.2.1]heptane-1-carboxylic acid (52 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Product: N#Cc1cc(NC(=O)c2ccn(-c3ccc(F)cc3)c2)ccc1N1CCC(N2CCOCC2)CC1
Yield: 34.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)pyrrole-3-carboxylic acid (0.5 g) and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (0.7 g), the title compound (0.4 g) was obtained, melting point: 182–183° C.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])=[N:25][N:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:26]2[O:27][C:23]([CH3:22])=[N:24][N:25]=2)[CH:29]=1)([O-:21])=[O:20]
Reactant: Cc1nnc(-c2cccc(N)c2)o1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: Cc1nnc(-c2cccc(Nc3ccc4ccccc4c3[N+](=O)[O-])c2)o1
Yield: 70.4 %

Procedure:
1-Nitronaphthalen-2-yl triflate (1.54 g, 4.8 mmol) and 3-(5-methyl-[1,3,4]oxadiazol-2-yl)aniline (0.84 g, 4.8 mmol) were used in a process similar to Example 1(1) to give the titled compound (1.17 g, yield 71%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][S:16]([CH2:19][CH2:20][CH2:21]O)(=[O:18])=[O:17]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:21][CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCO
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Product: CS(=O)(=O)CCCOc1cc2nccc(Cl)c2cc1C#N
Yield: 90.3 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 15, (see note a) above), 4-chloro-6-cyano-7-hydroxyquinoline (300 mg, 1.46 mmol), (prepared as described for the starting material in Example 1), was reacted with 3-(methylsulphonyl)-1-propanol (263 mg, 1.9 mmol) and the crude product was purified using a gradient of methylene chloride/ethyl acetate (1/1) to (2/8) to give 4-chloro-6-cyano-7-(3-methylsulphonylpropoxy)quinoline (428 mg, 90%)
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:13]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:12][CH:11]=[CH:10][C:9]=1[O:21][CH3:22])(=O)=O.C(#[N:25])C>>[CH3:22][O:21][C:9]1[C:8]2[CH2:7][CH2:6][NH:25][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC#N
Reactant: COc1cccc(CCOS(C)(=O)=O)c1CCOS(C)(=O)=O
Product: COc1cccc2c1CCNCC2
Temperature: 100 °C

Procedure:
Dissolve 2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g, 1.346 mol) in acetonitrile (7 L) and split the mixture into two equal lots. In two separate runs, add concentrated aqueous NH4OH (3.5 L) and charge the solution to a pressure vessel (Parr apparatus). Heat the solution in a closed reactor to 100° C. over 20 min (internal pressure reaches about 100 psi), and maintain at 100° C. until the reaction is complete (about 1 h, HPLC monitored). Cool the reaction mixture to ambient temperature. Combine the two lots and remove the solvent in vacuo. Dissolve the residue in MTBE (3.5 L) and water (3.5 L). Adjust the pH to 6.5 using 2M aqueous NaOH or 1M aqueous HCl as appropriate (typically the pH is about pH=5.1 and the adjustment requires about 50 mL 2M aqueous NaOH). Discard the organic layer, adjust the aqueous layer to pH=13 using 50% NaOH (about 150 mL). Extract with MTBE (2×3.5 L), wash the combined organic layers with brine (3.5 L), dry over Na2SO4, filter and concentrate in vacuo to give the title compound as a crude yellow oil that solidifies upon standing (179.3 g). Use the material for the next step without further purification. Prepare an analytical sample by purification by two Kugelrohr distillations to give a clear oil that solidifies upon standing, mp 44.3-45.0° C. 13C NMR (300 MHz, DMSO-d6), δ 156.1, 144.4, 130.3, 126.2, 121.5, 108.9, 55.5, 48.2, 47.9, 39.9, 29.1; MS (ES+) m/z 163 (M+H)+; Anal. Calc'd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.28, H, 8.62; N, 7.86.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[C-:23]#N.[K+]>C(O)C#C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][C:19]#[CH:23])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: C#CCO
Agent: [K+]
Product: C#CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reaction time: 1 h

Procedure:
A mixture of 20.0 g (65.9 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.0 g (15.4 mmol) of potassium cyanide and 100 ml of propargyl alcohol is stirred at 125° for 20 hours and at 135° for 1 hour, evaporated to dryness in vacuo and the residue is taken up in chloroform. The chloroform solution is washed twice with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the resulting material from chloroform/toluene there is obtained 2-propynyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 220°-222°.
Reaction SMILES: Cl.[CH2:2]([C:4]1([CH3:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)[CH3:3]>O.C(O)C.[Zn].C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:2]([C:4]1([CH3:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH3:3]
Reactant: CCC1(C)Cc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Hg+2]
Solvent: CCO
Solvent: O
Product: CCC1(C)Cc2ccccc2C1

Procedure:
335 g of zinc dust and 33.5 g of mercury (II) acetate and a solution of 330 cc of concentrated hydrochloric acid in 280 cc of water are rapidly added dropwise in a stirring apparatus. The mixture is boiled at reflux and a solution of 63 g of 2-ethyl-2-methyl-1-indanone in 525 cc of ethanol is added dropwise within 10 minutes while stirring. The reaction mixture is subsequently stirred at reflux for 28 hours, cooled, filtered, and the residue is washed with water/petroleum ether. The filtrate is extracted with petroleum ether, the petroleum ether extract is washed with water and dried over sodium sulphate. The crude 2-ethyl-2-methyl-indan, obtained as an oil after evaporating the solvent, is purified by chromatography on aluminium oxide/petroleum ether.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].CCCCCC.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=CC=CC=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C(OCC)C>[C:1]1([Li:5])[C:22]2[CH2:23][C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
With stirring, 113 ml of a 1.6 M solution of n-butyllithium in hexane (0.18 mol) were added to a solution of 25 g (0.15 mol) of fluorene in 220 ml of diethyl ether. To bring the reaction to completion, the mixture was boiled under reflux for 6 h and then stirred at room temperature overnight. The solvent was subsequently removed under reduced pressure and the resulting yellow powder was washed repeatedly with petroleum ether and dried under reduced pressure. This gave fluorenyllithium (compound II) in almost quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5](=[CH:8][C:9]=1[OH:10])[C:6]#[N:7].[CH2:13]([O:15][CH:16]([O:23][CH2:24][CH3:25])[CH2:17][CH:18]([CH2:21]O)[CH2:19]O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:24]([O:23][CH:16]([O:15][CH2:13][CH3:14])[CH2:17][CH:18]1[CH2:19][O:10][C:9]2[CH:8]=[C:5]([C:6]#[N:7])[C:4]([C:11]#[N:12])=[CH:3][C:2]=2[O:1][CH2:21]1)[CH3:25]
Reactant: N#Cc1cc(O)c(O)cc1C#N
Reactant: CCOC(CC(CO)CO)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(CC1COc2cc(C#N)c(C#N)cc2OC1)OCC
Temperature: 75 °C

Procedure:
To the mixture of 4,5-dihydroxy-phthalonitrile (2.50 g, 15.6 mmol), 2-(2,2-diethoxy-ethyl)-propane-1,3-diol (4.5 g, 23.4 mmol) and triphenylphosphine (6.138 g, 23.4 mmol) in THF (40 mL) was added diethyl azodicarboxylate (4.08 g, 23.4 mmol) and the resulting mixture heated at 75° C. overnight. The resulting mixture was then cooled to room temperature and evaporated in vacuo to yield a solid, which was purified via flash column chromatography (EA/Hex 2:3) to yield 3-(2,2-diethoxyethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7,8-dicarbonitrile as a white solid. MS MH+=317, 1H NMR (CDCl3) δ 7.29 (s, 2H), 4.58 (m, 1H), 4.46 (m, 2H), 4.19 (m, 2H), 3.66 (m, 2H), 3.52 (m, 2H), 2.60 (m, 1H), 1.78 (m, 2H), 1.20 (t, J=7.0 Hz, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][C:21]2[CH:25]=[CH:24][O:23][N:22]=2)[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:26][CH:27]1[C:37](=[O:38])[N:29]2[C:30]([C:34]([OH:36])=[O:35])=[CH:31][CH2:32][S:33][C@H:28]12.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O.O1CCCC1.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][C:21]2[CH:25]=[CH:24][O:23][N:22]=2)[C:15]([NH:26][CH:27]2[C:37](=[O:38])[N:29]3[C:30]([C:34]([OH:36])=[O:35])=[CH:31][CH2:32][S:33][C@H:28]23)=[O:17])[N:13]=1)=[O:7]
Reactant: O=CNc1nc(C(=NOCc2ccon2)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=CNc1nc(C(=NOCc2ccon2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 77.4 %

Procedure:
Phosphoryl chloride (1.02 g.), 2-(2-formamidothiazol-4-yl)-2-(3-isoxazolylmethoxyimino)acetic acid (syn isomer, 1.0 g.), N,N-dimethylformamide (0.448 g.) and tetrahydrofuran (10 ml.) were treated in a similar manner to that of Example 5-(1) to give an activated acid solution. On the other hand, a mixture of 7-amino-3-cephem-4-carboxylic acid (0.91 g.), tetrahydrofuran (10 ml.) acetone (5 ml.) and water (5 ml.) was adjusted to pH 7.5 with 20% aqueous sodium carbonate at 0° to -5° C. The activated acid solution was added dropwise to the above solution at 0° to -5° C. while keeping at pH 7.5 to 8.0. The mixture was treated in a similar manner to that of Example 5-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-isoxazolylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.25 g.).
Reaction SMILES: CI.[Mg].Br[CH2:5][C@@H:6]([CH3:16])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1>O1CCCC1>[CH3:16][C@H:6]([CH2:5][CH2:8][CH2:7][CH:6]([CH3:16])[CH3:5])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: C[C@H](CBr)CCOC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)CCC[C@@H](C)CCOC1CCCCO1
Reaction time: 0.08 h

Procedure:
4.7 g (0.202 mol) of magnesium shavings in a 3-necked flask under an argon atmosphere and provided with a calcium chloride tube are activated by addition of 2.0 ml of methyl iodide. After 5 minutes, the methyl iodide is removed and the magnesium washed several times with absolute tetrahydrofuran. To the activated magnesium is added dropwise a solution of 44 g (0.175 mol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 50 ml of absolute tetrahydrofuran at such a rate that the solvent just boils. Where the Grignard reaction does not start itself, it is warmed to 85° with the oil bath. After completed addition of 2-[(S)--4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, the mixture is stirred at 85° for so long (0-15 min.) until only traces of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran are still present in accordance with gas-chromatographical analysis. The solution obtained is cooled to -78° and treated dropwise with 21.2 g (0.0875 mol) of 3-methyl-1-butanol--p-toluenesulphonate followed by 3.6 ml of a 0.1 molar solution of Li2CuCl4 in absolute tetrahydrofuran. This reaction mixture is stirred at -78° during 10 min. then at 0° for 2 hours and subsequently at room temperature for a further 14 hours. For the working up of the 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran obtained the mixture is poured on to ice and brought to pH 5-6 with 2-N sulphuric acid. By three-fold extraction with ether and removal of the solvent on the rotary evaporator there is obtained a mixture of (R)-3,7--dimethyl-1-octanol and 2[(R)-3,7-dimethyloctanoxy]-tetrahydro--2H-pyran. This mixture is treated portionwise in 100 ml of methanol at 0° with a total of 100 ml of 7-N aqueous hydrochloric acid. After 2-hours stirring at room temperature, the mixture is neutralised with dilute aqueous caustic soda and extracted with ether. After chromatography on silicagel, deactivated with 0.5% ammonia, with pentane/ether (4:1), there are obtained 10.6 g (76% based on 3-methyl-1-butanol-p-toluenesulphonate employed) of pure (R)-3,7-dimethyl-1-octanol. B.p. 58°-59°/0.05 Torr; [α]D20 =+4.0 (c=1.03, CHCl3).
Reaction SMILES: [C:1]([CH:4]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[CH3:10])[C:5](OC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:9]([C:4]3[C:5](=[O:6])[N:26]=[N:27][C:1]=3[CH3:2])[CH3:10])[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)C(C(C)=O)C(C)c1ccc(OC)c(OC2CCCC2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)C2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
To a stirred solution of methyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-butanoate (362 mg, 1.08 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (54 mg, 1.08 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. Further hydrazine monohydrate (15.6 mg, 3.1×10−4 mol) was added and refluxing continued for a further 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2; methylene chloride/ethanol/ammonia (97.5:2.5:0.25)) to afford the title compound as a white solid (76 mg).
Reaction SMILES: [C:1]([N:4]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3C(OCC3C=CC=CC=3)=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:38])[CH2:6]1)(=[O:3])[CH3:2]>Br.C(O)(=O)C>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([N:4]([C@H:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([CH:23]4[CH2:27][CH2:26][CH2:25][NH:24]4)=[CH:21][CH:22]=3)[C@@H:7]([CH3:38])[CH2:6]2)[C:1](=[O:3])[CH3:2])=[CH:40][CH:41]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C3CCCN3C(=O)OCc3ccccc3)cc2)c2ccccc21
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C3CCCN3)cc2)c2ccccc21
Reaction time: 2 h
Yield: 91.4 %

Procedure:
Benzyl 2-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)pyrrolidine-1-carboxylate (237 mg, 0.381 mmol) was dissolved in HBr/Acetic acid (5 mL) and stirred for 2 h. The reddish slurry was partitioned between Et2O and 1N HCl. The HCl/water layer was washed 3× with Et2O to rid the benzyl bromide. The water layer was neutralized with 1N NaOH, and washed 3× with methylene chloride. The organic layer was dried over MgSO4, filtered and concentrated to afford the title compound (170 mg, 91%) as a white solid. 1H-NMR (CDCl3) δ: 1.05-1.20 (m, 1H), 1.13 (s, 3H), 1.50-1.62 (m, 1H), 1.76-1.90 (m, 2H), 2.02 (s, 3H), 2.05-2.20 (m, 2H), 2.20-2.38 (m, 1H), 2.93-3.03 (m, 1H), 3.09-3.18 (m, 1H), 4.05 (t, 1H), 4.72-4.82 (m, 1H), 5.45-5.75 (m, 1H), 6.49 (d, 1H), 6.88 (t, 1H), 7.11-7.29 (m, 8H), 7.37 (d, 2H).
Reaction SMILES: F[C:2]1[C:3](=[CH:17][C:18]([F:23])(C)[CH:19]([F:21])[CH:20]=1)[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:14]1([N:13]2[C:2]3[C:3](=[CH:17][C:18]([F:23])=[C:19]([F:21])[CH:20]=3)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)C1=CC(C)(F)C(F)C=C1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
A solution of 7.2 g (22 mmol) of ethyl 2-(2,4,5-trifluoro-5-methylbenzoyl)-3-cyclopropylaminoacrylate in 100 mL of dry t-butanol was treated portionwise with 2.8 g (25 mmol) of potassium t-butoxide, and the reaction mixture was stirred at 60° C. for 5 hours. The suspension was cooled to room temperature and concentrated. The residue was partitioned between dichloromethane and 1N hydrochloric acid; the organic phase was washed with water, dried over magnesium sulfate, and concentrated. The crude product was slurried in boiling ethanol, filtered, and air-dried to give 4.2 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][NH2:36]>>[CH3:35][NH:36][C:29](=[O:31])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:34])[F:33])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CN
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CNC(=O)C(C)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid (prepared from the procedure for Example 54, step 2) and methylamine (2.0 N in THF). LCMS (M+H)+: m/z=487.2.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:12]3)C=CC=[CH:3][CH:2]=1.C1(B(O)O)CC1>>[CH:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:23])([CH3:24])[O:17]2)=[CH:12]3)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cc3cccc(-c4ccccc4)c3[nH]2)OC1(C)C
Agent: OB(O)C1CC1
Product: CC1(C)OB(c2cc3cccc(C4CC4)c3[nH]2)OC1(C)C

Procedure:
Prepared according to the procedures described above for 7-phenyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using cyclopropylboronic acid in place of phenylboronic acid. 1H NMR (CDCl3, 400 MHz): δ 0.75-0.82 (m, 2H), 0.95-1.04 (m, 2H), 2.08 (m, 1H), 6.59 (dd, J=3.0, 2.0 Hz, 1H), 6.96 (d, J=7.1 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 7.25 (m, 1H), 7.52 (d, J=7.8 Hz, 1H) and 8.39 (br s, 1H) ppm. LC-MS (ES, Pos.): 158 [MH30 ].
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][C@H:46]([CH3:50])[CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH2:37]([N:44]1[CH2:49][CH2:48][N:47]([C:21]2[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([CH3:34])[CH3:33])=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[CH:22]=2)[C@H:46]([CH3:50])[CH2:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCN(Cc3ccccc3)C[C@H]2C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 36.4 %

Procedure:
A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 93 mg (0.49 mmol) (R)-1-benzyl-3-methyl-piperazine, 0.01 g (0.03 mmol) cetyltrimethyl-ammonium bromide, 0.038 g (0.074 mmol) bis(tri-t-butylphosphine)palladium(0), 0.05 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. for 48 h. After cooling to room temperature the mixture was diluted with water and brine and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 95 mg (37%) of the title compound as a light yellow solid. MS m/e (%): 687 (M+H+, 100)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.C1COCC1.NN>C(O)C.[Ni]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[CH:14]([O:13][C:6]1[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([NH2:1])[CH:5]=1)[CH2:15]2
Reactant: O=[N+]([O-])c1cc(OC2CN3CCC2CC3)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(OC2CN3CCC2CC3)c2occc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
3-[(5-Nitro-1-benzofuran-7-yl)oxy]quinuclidine (1.38 g, 4.79 mmol; obtained in Step 1) was dissolved in ethanol:THF (100 mL: 25 mL) and Raney-nickel (slurry in ethanol; 6 mL) and hydrazine (891 μL, 0.18 mmol) were added. The mixture was stirred at room temperature for 3 h and then filtered through Celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: DCM:methanol (6:1) and chloroform:MeOH:triethylamine (9:1:0.1)] to give 7-(1-azabicyclo[2.2.2]oct-3-yloxy)-1-benzofuran-5-amine (500 mg; 40%).