Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:40])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH2:30])([CH3:26])([CH3:25])[CH3:24].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:40])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:30][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:21][CH:20]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-(benzyloxycarbonylaminomethyl)benzoic acid as obtained in Reference Example 35 (1.0 g), glutamic acid di-t-butyl ester hydrochloride (1.15 g) and DEPC (860 mg) in dimethylformamide (20 ml), triethylamine (1.06 g) was added drop by drop, followed by stirring at room temperature for 1 hour. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield the title compound (1.86 g, yield 100%) as a colorless wax-like substance.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[CH:10][C:11](F)=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([OH:20])[C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([O:38]CC)(=[O:37])[CH2:35][SH:36].O>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[CH:10][C:11]([S:36][CH2:35][C:34]([OH:38])=[O:37])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([OH:20])[C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(F)cc2C(c2ccccc2)C1O
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(SCC(=O)O)cc2C(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.3 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-fluoro-2,3,4,5-tetrahydrobenzothiepine (prepared according to WO 98/40375; 300 mg, 0.77 mmol) was dissolved in DMF (3 ml) and caesium carbonate (540 mg, 1.66 mmol) was added followed by ethyl thioglycolate (0.17 ml, 1.54 mmol) and the reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 100° C. for 5 min. The reaction mixture was added to water (25 ml), extracted with DCM (5×5 ml) and concentrated. The crude ethyl ester was dissolved in THF (4 ml) and water (2 ml) and NaOH (1 M, 4 ml) was added. The reaction mixture was stirred at ambient temperature for 6 hours, quenched with HCl (1 M), diluted with water (25 ml) and extracted with DCM (4×5 ml). The combined organic layers were purified with preparative HPLC using MeCN/ammonium acetate buffer as the eluent (50:50) to give the title compound (172 mg, 48%). NMR (400 MHz, DMSO-d6): 0.74 (t, 3H), 0.84 (t, 3H), 1.01 (m, 1), 1.18-1.46 (m, 5H), 1.60 (m, 1H), 2.02 (m, 1H), 3.07/3.12 (ABq, 2H), 3.33/3.39 (ABq, 2H), 3.95 (s, 1H), 5.23 (s, 1H), 6.38 (d, 1H), 7.19 (dd, 1H), 7.34 (m, 1H), 7.42 (m, 4H), 7.73 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][N:12]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[CH3:13])[CH:3]=1)=[O:6])[CH3:9]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccnc(-c2ccc(F)cc2C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
In a mixed solvent of 250 ml of toluene and 50 ml of ethanol were dissolved 20 g of ethyl 2-chloroisonicotinate and 20 g of 2-methyl-4-fluorophenylboronic acid, and 5.8 g of palladium tetrakistriphenylphosphine and 250 ml of a 2M aqueous sodium carbonate solution, and the mixture was stirred at 50 to 70° C. for 2 hours. The solution was cooled down to room temperature and extracted by adding ethyl acetate and water. The organic layer was further washed with water, and dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1), to give 24.8 g of 4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)pyridine as shown in Table 132 below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.C[N:15](C)CCCN=C=NCC.ON1C(=O)CCC1=O.N>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([NH2:15])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: N
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
3,4,5-Trifluorobenzoic acid (1.00 g) was dissolved in N,N-dimethylformamide (15 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.31 g) and N-hydroxysuccinimide (785 mg) were added thereto at 0° C. The mixture was stirred at room temperature for 3 hr. 28% Aqueous ammonia solution (2 mL) was added to the mixture at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane=1:2→3:1) and recrystallized from a mixed solvent of isopropylether and hexane to give the title compound as colorless crystals (yield: 734 mg).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([O:17][C:18](=[O:24])NCCCC)([C:15]#[CH:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:25]1CCOCC1>>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2([O:17][C:18](=[O:24])[O:25][C:15]2=[CH2:16])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C#CC1(OC(=O)NCCCC)CCN(Cc2ccccc2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Dry gaseous hydrogen chloride is introduced at 20° to 50° C. during 2.5 to 3 hours into a solution containing 31.4 g of 1-benzyl-4-butylcarbamoyloxy-4-ethynylpiperidine in 157 ml of anhydrous dioxane. After standing overnight the reaction mixture is evaporated in a water bath of 40° to 50° C. temperature under reduced pressure. After adding 200 ml of water to the evaporation residue the base is liberated by sodium hydrogen carbonate. After filtration the solid precipitate is washed to chloride-free with water and dried. The crude product obtained is recrystallized from n-hexane under clarifying by activated carbon to give the title compound in 80.6% yield, m.p.: 65°-67° C.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[CH3:8][C:9]1[C:10]([CH2:20][C:21]#[N:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1.CO>C1COCC1>[CH3:8][C:9]1[C:10]([CH2:20][CH2:21][NH2:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1
Reactant: Cc1cn(-c2ccccc2)nc1CC#N
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(-c2ccccc2)nc1CCN
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To lithium borohydride (2M solution in THF, 629 μL, 1.26 mmol) was added dropwise trimethylchlorosilane (273 mg, 321 μL, 2.51 mmol) over a period of 5 min at 0-5° C. At that temperature a solution of 2-(4-methyl-1-phenyl-1H-pyrazol-3-yl)acetonitrile (62 mg, 314 μmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at 70° C. for 1.5 h. After cooling down to 0-5° C., MeOH (0.5 mL) was added dropwise. After 10 min the ice bath was removed and the mixture was allowed to warm up to RT. The reaction mixture was poured into NaOH (1 M, 10 mL) and extracted with dichloromethane (3×25 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as light yellow semisolid (46 mg, 206 μmol, 65.4%) which was used without further purification for the next step.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8]Cl)[N:4]1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOCCOC.C(OCC)C>[CH2:23]([N:30]1[CH2:8][CH:5]2[N:4]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:3]([CH2:7][CH2:6]2)[CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCC1CCC(CCl)N1c1ccc(Cl)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: Clc1ccc(N2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
2,5-Bis-chloromethyl-1-(4-chlorophenyl)-pyrrolidine (3.73 g, 13.57 mmol), potassium carbonate (3.75 g, 27.14 mmol), and benzyl amine (4.45 mL, 40.71 mmol) in diglyme (25 mL) was heated at reflux for 15 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (600 mL) and washed with water (6×300 mL). The combined organic layers were dried with magnesium sulfate and concentrated to a brown oil. Silica gel flash chromatography using 50% chloroform/hexanes as eluent yielded 3-Benzyl-8-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane (1.0 g, 23.5%) as a golden solid which had the following properties: Mp. 115-117° C.; 1H NMR CDCl3 δ: 7.29 (s, 5H), 7.14 (d, J=8.1 Hz, 2H), 6.67 (d, J=8.3 Hz, 2H), 4.08 (brd s, 2H), 3.38 (s, 2H), 2.54-2.42 (m, 4H), 2.08-2.00 (m, 2H), 1.95-1.86 (m,2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]1[C:11]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:9]=[CH:8][C:7]=1[F:17].[OH:19]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]1[C:7]([F:17])=[CH:8][CH:9]=[CH:10][C:11]=1[S:12]([C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)Sc1cccc(F)c1C(=O)NCCCl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)c1cccc(F)c1C(=O)NCCCl
Reaction time: 0.03 h
Yield: 98 %

Procedure:
A 0° C. solution of N-(2-chloroethyl)-2-fluoro-6-(1,1-dimethylethylthio)benzamide (2.0 g, 7.0 mmol) in methanol (50 mL) was combined with a 0° C. solution of OXONE® (4.24 g, 7.0 mmol) in water (50 mL). This mixture was stirred for 2 min, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then were dried (MgSO4), concentrated, and purified by HPLC with 7:3 ethyl acetate/hexanes to afford 2.1 g of the title compound as a white solid, a 98% yield. m.p. 80°-90° C.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(O)cccc2C1=O
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A mixture of 2,2-dibutyl-3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (2.643 g), 2-chloromethylquinoline (1.7 g), and potassium carbonate (1.67 g) in N,N-dimethylformamide (16 ml) was stirred at 80° C. for 4 hours. The cooled mixture was poured into water. The separated oil was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated in vacuo. The crude product was chromatographed on silica gel using 25% ethyl acetate in n-hexane as eluent to yield 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (3.09 g) as a pale yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=3)[CH:16]=[C:17]([OH:19])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].[C:30]([OH:35])(=O)[C:31]([CH3:33])=[CH2:32]>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])=[CH2:32])=[CH:22][CH:21]=3)[CH:16]=[C:17]([O:19][C:30](=[O:35])[C:31]([CH3:33])=[CH2:32])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:30](=[O:35])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)O
Reactant: OCCCOc1ccc(-c2cc(O)cc(-c3ccc(OCCO)cc3)c2)cc1F
Product: C=C(C)C(=O)OCCCOc1ccc(-c2cc(OC(=O)C(=C)C)cc(-c3ccc(OCCOC(=O)C(=C)C)cc3)c2)cc1F

Procedure:
In analogy to step 2 of Example 1, 3″-fluoro-4-(2-hydroxy-ethoxy)-4″-(3-hydroxy-propoxy)-[1,1′;3′,1″]terphenyl-5′-ol and methacrylic acid are reacted to give 2-methyl-acrylic acid-3-{3″-fluoro-5′-(2-methyl-acryloyloxy)-4-[2-(2-methyl-acryloyloxy)-ethoxy]-[1,1′;3′,1″]terphenyl-4″-yloxy}-propyl ester as colourless crystals with a m.p. 70° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:34])[C@H:16]([CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=1)[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20].[C:35]1([C:41]2[O:42][C:43]3[C:49]([CH2:50]O)=[CH:48][CH:47]=[CH:46][C:44]=3[N:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:34])[C@H:16]([CH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([O:32][CH2:50][C:49]2[C:43]3[O:42][C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:45][C:44]=3[CH:46]=[CH:47][CH:48]=2)=[C:29]([Cl:31])[CH:30]=1)[NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21]
Reactant: OCc1cccc2nc(-c3ccccc3)oc12
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCc2cccc3nc(-c4ccccc4)oc23)c(Cl)c1)NC(=O)C(F)(F)F
Reaction time: 60 h
Yield: 81.6 %

Procedure:
Diethylazodicarboxylate (40% toluene solution 0.63 ml) was added dropwise to a solution of 3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (252 mg, 0.7 mmol), [(2-phenyl)-benzoxazol-7-yl]methanol (193 mg, 0.857 mmol) and triphenylphosphine (374 mg, 1.43 mmol) in tetrahydrofuran (3 ml) under argon atmosphere at 5° C., and the mixture was stirred at the same temperature for 60 hrs. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4) to give 3,5-dichloro-N-trifluoroacetyl-O-[(2-phenyl)-benzoxazol-7-yl]methyl-L-tyrosine methyl ester (324 mg, 82%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>ClCCl>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: NCCCN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: ClCCl
Product: NCCCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1,3-diaminopropane (6.7 mL) in 100 mL of dichloromethane at −10° C. was slowly added over a 2 hour period a solution of 4-(4-fluorophenoxy)benzenesulfonyl chloride (5.7 g, 20 mmol) in 50 mL of dichloromethane. The reaction was stirred for 15 minutes after the addition was complete, and then partitioned between ethyl acetate and water. The resulting emulsion was cleared by addition of dichloromethane, and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were extracted with 0.5 N aq. sodium bisulfate. The aqueous phase was brought to pH 8 with sodium bicarbonate and then extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to a volume of about 50 mL. Addition of hexane resulting in formation of a precipitate, which was collected by filtration to provide N-(3-aminopropyl)-4-(4-fluorophenoxy)benzenesulfonamide (4.27 g) as a white solid: mp 184° C. (softens), 237° C. (melts) 1H NMR (300 MHz, DMSO-d6): δ 7.84 (d, J=9 Hz, 2H), 7.38-7.21 (m, 4H), 7.12 (d, J=9 Hz, 2H), 3.6-3.2 (br s, 3H), 2.80 (dd, J=7, 7 Hz, 2H), 2.77 (dd, J=7, 7 Hz, 2H), 1.72-1.60 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16]([NH:19][C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[CH:22][C:21]=2[N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH2:49])[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:49][C:44]1[N:43]=[C:42]([C:24]2[CH:23]=[CH:22][C:21]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[CH3:18])[CH:25]=2)[CH:47]=[C:46]([CH3:48])[N:45]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCOCC1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(N3CCOCC3)c(Nc3c(C)c(-c4ccccc4F)nc4ccccc34)c2)nc(N)n1
Temperature: 120 °C

Procedure:
A solution of 2-(2-fluorophenyl)-3-methyl-N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-4-amine (100 mg, 0.185 mmol; described herein), 4-chloro-6-methylpyrimidin-2-amine (26.6 mg, 0.185 mmol), sodium carbonate (58.9 mg, 0.556 mmol), dichlorobis(triphenylphosphine)-palladium(ii) (13.0 mg, 0.019 mmol), 1,4-dioxane (4.0 mL), and water (1.0 mL) was heated in a microwave at 120° C. for 60 min. The mixture was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concd, and chromatography afforded N-(5-(2-amino-6-methyl-4-pyrimidinyl)-2-(4-morpholinyl)phenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine. 1H NMR (400 MHz, TFA) δ ppm 8.32 (1H, dd, J=8.8, 2.2 Hz), 7.95-8.17 (5H, m), 7.72 (2H, m), 7.55 (1H, m), 7.40-7.48 (1H, m), 7.24-7.37 (2H, m), 4.30-4.47 (4H, m), 4.07-4.25 (4H, m), 2.60 (3H, s), 2.09 (3H, br. s.). Mass Spectrum (ESI) m/e=521.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:27]3[N:28]=[N:29][CH:30]=[N:26]3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=416.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>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]>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 62.9 %

Procedure:
The general procedure from Example 9 was followed using 4-methylchlorobenzene (152 mg, 1.2 mmol) and PhB(OH)2 (1.2 mmol) with Pd2 (dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) from Experiment 2 (14.5 mg, 0.0878 mmol) and CsCO3 (651 mg, 2.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 127 mg (63% yield) of 4-phenyltoluene. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, J=7.50 Hz, 2H), 7.65 (d, J=8.05 Hz, 2H), 7.57 (m, 2H), 7.47 (m, 1H), 7.40 (m, 2H), 2.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 141.1, 138.3, 136.9, 129.4, 128.6, 126.9, 126.8, 21.0 ppm.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:9]C1C=CC(OC)=CC=1.CN(C=O)C>C1COCC1.[Zn+2].[Br-].[Br-].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>[I:9]/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Reactant: COc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCC/C=C/I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of oct-1-yne (56.2 mg, 0.5 mmol) and Cp2ZrCl2 (206.7 mg, 1.4 mmol, 1.4 eq.) in THF (2.5 mL) at RT was rapidly added a 1 M THF solution of LiAlH(Ot-Bu)3 (0.7 mL, 1.4 mmol, 1.4 eq.). A resulting dark red solution was stirred at RT for 15 min. At that time, dry ZnBr2 (157.7 mg, 1.4 mmol, 1.4 eq., Aldrich) and THF (1 mL) were added at RT. After 30 min., 1-iodo-4-methoxybenzene (165.5 mg, 1.4 mmol, 1.4 eq., Aldrich), Pd(PPh3)4 (11.6 mg, 0.001 mmol, 0.02 eq.) and DMF (1 mL) were added. The resultant mixture was stirred at RT for 5 h and then quenched with 1 N HCl, and extracted with EtOAc (4×5 mL). Organic extracts were combined and washed with H2O and brine, dried over MgSO4 and concentrated via evaporation under reduced pressure. Purification of the residue was performed using a silica gel column (silica gel 60, 230-400 mesh) with CH2Cl2/hexanes as eluent. (E)-1-iodooct-1-ene (41.3 mg, 38% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 7.27 (d, J=8.62 Hz, 21-1), 6.83 (d, J=8.64 Hz, 2H), 6.31 (d, J=15.79 Hz, 1H), 6.08 (dt, J=14.23, 6.89 Hz, 1H), 3.79 (s, 3H), 2.17 (td, J=7.14, 7.07 Hz, 2H), 1.50-1.40 (m, 2H), 1.38-1.27 (m, 6H), 0.89 (t, J=6.31 Hz, 3H) 13C NMR (101 MHz, CDCl3) δ ppm: 158.59, 130.84, 129.09, 128.99, 126.93 (2C), 113.89 (2C), 55.27, 33.02, 31.77, 29.50, 28.91, 22.63, 14.09. Physical and spectral data were consistent with those previously reported (see Nakao, Y.; Imanaka, H.; Sahoo, A. K.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 6952-6953.)