Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5]([OH:7])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:28][C:20]1[C:21]([C:5](=[O:7])[C:4]2[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)cccc2C(F)(F)F)c(OC)c1OC

Procedure:
65A (1.38 g, 0.00625 mol) is reacted with 3,4,5-trimethoxytoluene (1.14 g; 0.00625 mol) in the presence of P2O5 (5.0 g) and dichloromethane (100 ml) as described in Example 6 yielding white crystals, 1.68 g (69.8% ), mp 69-70° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[C:5]1([O:4][C:2](=[O:3])[NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(Oc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of phenyl chloroformate (0.29 mL, 2.3 mmol) in tetrahydrofuran (10 mL) were added 3-phenoxybenzylamine described in Preparation Example 4 (0.5 g, 2.5 mmol) and triethylamine (0.35 mL, 2.5 mmol) dropwise on an ice bath, and then, the solution was stirred at room temperature for 4 hours. The reaction solution was poured into brine, the solution was extracted with ethyl acetate and concentrated, and the title compound (0.7 g, 2.2 mmol, 88%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([Cl:14])=[O:10])[O:5][N:4]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 3-methoxyisoxazole-5-carboxylic acid (420 mg, 3 mmol) in THF (15 mL) and DMF (5 drop) was added dropwise oxalyl chloride (650 μL, 7 mmol) at 0° C. The mixture was then stirred at room temperature for 3 hours. The solution was concentrated in vacuo to yield the title compound as a light yellow oil (430 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:43])([CH3:42])[C@H:3]([NH:30][C:31]([C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][N:16]=1)=[O:14])=[O:5].Br[C:45]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:51][C:50]1[C:45]([C:18]2[CH:17]=[N:16][C:15]([C:13]([N:9]3[CH2:8][C@@H:7]4[CH2:12][C@H:10]3[CH2:11][N:6]4[C:4]([C@@H:3]([NH:30][C:31]([C:33]3[NH:34][C:35]4[C:40]([CH:41]=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[C:2]([CH3:1])([CH3:42])[CH3:43])=[O:5])=[O:14])=[CH:20][CH:19]=2)=[N:46][CH:47]=[CH:48][CH:49]=1
Reactant: Fc1cccnc1Br
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ncccc2F)cn1
Yield: 14.6 %

Procedure:
A mixture of N-{(1S)-2,2-dimethyl-1-[((1S,4S)-5-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]carbonyl}-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl]propyl}-1H-indole-2-carboxamide (150 mg, 0.26 mmol), 2-bromo-3-fluoropyridine (69 mg, 0.38 mmol), Pd(dppf)Cl2 (15 mg, 0.018 mmol), sodium carbonate (55 mg, 0.52 mmol) in dry 1,4-dioxane (2 mL) and water (1 mL) was refluxed for 16 h under a nitrogen atmosphere. The solution was concentrated and the resulting residue was purified by reverse phase HPLC. Concentration of the desired fractions containing product afforded the title compound (21 mg) as a pale brown solid. LCMS (m/z): 555.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm: 0.90-1.10 (m, 9H), 1.80-2.25 (m, 2H), 3.50-4.30 (m, 4H), 4.15-5.10 (m, 3H), 7.00-7.75 (m, 8H), 7.95-8.70 (m, 3H), 9.00-9.30 (m, 1H), 9.40-9.70 (m, 1H)
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:35])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].I[CH3:39]>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:35][CH3:39])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a 0° C. suspension of tert-butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxypiperidine-1-carboxylate (0.033 g, 0.069 mmol) in 2 mL DMF was added 60% NaH in mineral oil (0.0117 g, 0.486 mmol). The reaction mixture was warmed to ambient temperature and stirred 2 hours. Neat iodomethane (0.035 mL, 0.56 mmol) was added, and the reaction mixture was stirred for 21 hours. The reaction mixture was concentrated, and the residue was diluted with saturated NR4Cl and extracted with dichloromethane. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (0.5 mm plate, 9:1 dichloromethane:methanol) to give the title compound (0.016 g, 47.1% yield) as a yellow residue.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)OCC5C=CC=CC=5)[C@H:22]([F:37])[CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O.C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH:22]([F:37])[CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(N[C@H]1CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1F)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NC1CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)CC1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To the product from Step G (0.185 g, 0.373 mmol) was added HCl (1.86 mL, 11.2 mmol, 6.0M aqueous) and the solution was warmed to 90° C. and stirred for 0.5 hours. The mixture was cooled to ambient temperature and diluted with water (10 mL) and with CH2Cl2 (10 mL). The layers were mixed and separated and the aqueous phase was treated with saturated aqueous Na2CO3 until pH=10. The aqueous phase was extracted with CH2Cl2 (4×10 mL). The combined organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography (1 to 10% MeOH w/6% NH4OH/CH2Cl2) to afford 0.094 g (69%) of the desired product as a pale yellow/orange solid. MS ESI (+) m/z 363.2 (M+1) detected.
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13]C(=O)C)[CH:10]=[CH:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].C(=O)(O)[O-]>C(O)C.C(Cl)(Cl)Cl>[C:2]([O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1)(=[O:1])[CH3:3]
Reactant: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(=O)O[C@H]1C=C[C@@H](O)C1
Yield: 74.5 %

Procedure:
Dissolve (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (192 mg, 0.85 mmol, prepared in example 11) in ethanol (1.5 mL) and treat with p-toluenesulfonic acid (11.7 mg). Stir the reaction at room temperature for 2 hours. Add carbonate or bicarbonate to neutralize the reaction mixture and concentrate under vacuum. Purify the residue by chromatography (silica gel, 3 g, 1.5×3 cm column, 33% ethyl acetate/hexane, 80 mL), to provide the title compound (90 mg, 75% yield, 91% ee), [α]20D =-66.1°, (c=0.63, chloroform).
Reaction SMILES: [Cl:1][C:2]1[C:6](Cl)=[N:5][S:4][N:3]=1.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O.Cl>[Cl:1][C:2]1[C:6]([O:15][CH2:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[N:5][S:4][N:3]=1
Reactant: Clc1nsnc1Cl
Reactant: OCc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Clc1nsnc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
3,4-Dichloro-1,2,5-thiadiazole (2.00 mL, 21.3 mmol) was dissolved in 70 mL of t-butanol along with 4-pyridine methanol (1.05 g, 9.62 mmol). 30 mL of 1.0 M potassium t-butoxide (30 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with 100 mL of water and neutralized with 1.0 M HCl. The product was extracted 3 times with 100 mL portions of ethyl acetate. The combined organic fractions were dried with magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with a 2:1 solution of hexanes in ethyl acetate, affording 4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (821 mg) as an off-white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[N:9]([C:13]([C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:7]2[C:8]3[N:9]([C:13]([C:16]#[C:17][Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)C#Cc1cnc2c(OS(=O)(=O)C(F)(F)F)cccn12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[Si](C)(C)C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 80 °C

Procedure:
A mixture of 3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-8-yl trifluoromethanesulfonate (0.329 g, 0.91 mmol), 0.186 (1.09 mmol) of 4-(methylsulfonyl)aniline, 0.083 g (0.091 mmol) of Pd2(dba)2, 0.087 g (0.181 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and 0.385 g (1.81 mmol) of potassium phosphate in 8 mL of DME was heated at 80° C. in a sealed tube overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 0-80% EtOAc/hexanes) to provide 0.058 g of product: 384 m/z (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][NH:15][CH2:16][C@@H:17]([OH:32])[C@@H:18]([NH:28][C:29](=[O:31])[CH3:30])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.[ClH:51]>C1(C)C=CC=CC=1.CCOCC>[ClH:51].[C:38]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][NH:15][CH2:16][C@@H:17]([OH:32])[C@@H:18]([NH:28][C:29](=[O:31])[CH3:30])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH:3]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(Br)ccc1-c1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(C(C)=O)ccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To N-[(1S,2R)-3-{[(4-bromo-1,1′-biphenyl-2-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide (120 mg, 0.24 mmol) in toluene (1 mL) was added tributyl(1-ethoxyvinyl)tin (100 μL, 0.28 mmol) and bis-triphenylphoshine palladium(II) dichloride (10 mg, 0.012 mmol), and the reaction was heated at 100° C. 3 h under N2. The solution was cooled to room temperature, 1N hydrochloric acid (1 mL) was added, and the mixture was stirred 20 min. The mixture was partitioned, and the organics were washed with saturated potassium fluoride (aq). The reaction mixture was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 8% methanol/methylene chloride) provided an oil. The residue was dissolved in ether, precipitated with excess 1N HCl in ether, and concentrated to provide the title compound (11 mg). ESI MS m/z 467.28 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[N:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[N:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)Cc1nnc(-c2ccc([N+](=O)[O-])c(OC)c2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2nnc(CC(=O)O)[nH]2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 140 mg of ethyl [5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetate, 5 ml of methanol and 1 ml of 1N sodium hydroxide was stirred at room temperature for 2 hours. Afterwards, the volatile fractions are removed on a rotary evaporator, the residue is diluted with 10 ml of water and adjusted to pH 5 using 1N hydrochloric acid. The solid was filtered off with suction after the stirring.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[N:3][CH:4]=[C:5]([CH:9]=2)[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5c, using 6-chloro-5-(4-chloro-phenyl)-nicotinic acid and 2,2,2-trifluoro-ethanol as starting materials, MS (ISP) 330.3 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C([O-])(=O)C.[Na+].[OH-].[Na+]>COCCOC.O.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:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)ccc1F
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.0 g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.10 g, 10%) as white crystals. mp: 264-266° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.3 (dd, 1H, J=2.4, 3.7 Hz), 8.1-8.0 (m, 1H), 7.6-7.5 (m, 2H), 7.5 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([O:37][CH3:38])[CH2:31][CH2:32][C:33](OC)=[O:34]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][CH:30]([O:37][CH3:38])[O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)CCC(OC)OC
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: COC(CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)OC

Procedure:
The title compound, white solid (114 mg, 99%), MS (ISP) m/z=461.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 2 from trans-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl 4,4-dimethoxy-butanoate.
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]=[C:22]1[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][S:23]1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: ClCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2Cc2ccccc2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:17]([O-])([O-])([O:19][CH3:20])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[N:1]=[C:17]([O:19][CH3:20])[CH3:18]
Reactant: COC(C)([O-])[O-]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(C)=Nc1ccccc1C(=O)c1ccccc1Cl

Procedure:
A solution of 20 parts of 2-amino-2'-chlorobenzophenone, 15 parts of methyl orthoacetate, 12 volume parts of acetic acid in 250 parts of benzene is refluxed for 5 hours. The mixture is washed with saturated aqueous sodium bicarbonate solution and water, and then dried over sodium sulfate. Evaporation of the solvent gives 2'-chloro-2-(1-methoxyethylideneamino) benzophenone as an oily substance in almost quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[N+:20]([O-:34])[CH:21]=[CH:22][C:23]=1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of tert-butyl{4-chloro-2-[(4-methylpyridin-3-yl)ethynyl]phenoxy}acetate (Intermediate 19; 110 mg; 0.31 mmol) in DCM (5 mL) was treated with 3-chloroperbenzoic acid (91 mg; 0.37 mmol) and stirred at RT for 2 hours. The solvents were removed under vacuum, the residue was taken up in EtOAc and the organic phase washed with a saturated bicarbonate solution twice, then with brine. The organic layer was then dried over MgSO4 and concentrated under vacuum to afford the title compound (110 mg, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@@:9]3([CH2:15][N:14]4[CH2:16][CH2:17][CH:11]3[CH2:12][CH2:13]4)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].N#N>COCCOC.O.CCO.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:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:23]3[S:24][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)[CH:3]=[C:4]2[CH2:10][C@:9]21[CH2:15][N:14]1[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)s1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
To a stirred solution of (2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine] (Scheme 1, 3.2 g, 10.8 mmol) and (5-formyl-2-thienyl)boronic acid (3.37 g, 21.6 mmol) in 150 mL DME/H2O/EtOH (7:3:2), powdered Na2CO3 (4.58 g, 43.2 mmol) was added. The resulting mixture was purged with N2 at rt for 15 min, before the addition of dichloro[bis(triphenylphosphoranyl)]palladium (380 mg, 0.54 mmol). The reaction mixture was purged with N2 for another 15 min, before being heated in a 70° C. oil bath under N2 for 3-4 h. The reaction mixture was cooled and then concentrated under reduced pressure. The solid residue was treated with 150 mL CHCl3, and the resulting suspension was filtered through a short pad of diatomaceous earth (the filter cake was washed with ˜100 mL CHCl3). The combined filtrate was concentrated under reduced pressure. The blackish solid was taken into 0.5 M HCl (100-150 mL) and EtOAc (˜100 mL). The acidic aqueous layer was separated and the blackish organic layer was washed further with 0.5 M HCl (2×50 mL). The combined aqueous layers were then basified with 1 M NaOH to pH ˜12, and extracted with CHCl3 (100 mL, then 2×50 mL). The CHCl3 extracts were dried over MgSO4, filtered, and concentrated to give 3.5 g (99%) of 5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 1.50 (dddd, J=12.8, 10.7, 6.7, 2.3 Hz, 1H), 1.68-1.72 (m, 2H), 2.03 (t, J=2.9 Hz, 1H), 2.22-2.26 (m, 1H), 2.78-2.95 (m, 3H), 2.97 (dd, J=14.7, 2.1 Hz, 1H), 3.01-3.05 (m, 1H), 3.08 (d, J=16.5 Hz, 1H), 3.40 (dd, J=14.7, 1.6 Hz, 1H), 3.48 (d, J=16.5 Hz, 1H), 7.29 (d, J=4.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 9.88 (s, 1H); MS ES+ m/z=327 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1.[C:36](#[N:38])C>O>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:36]#[N:38]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccccc1-c1ccccc1

Procedure:
2-(Bromomethyl)biphenyl (1.35 g, 5.48 mmol), potassium cyanide (368 mg, 5.65 mmol), and a catalytic amount of 18-crown-6 ether were added to acetonitrile (10 ml), and the mixture was heated under reflux for 5 days. The reaction mixture was added with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as colorless solid (1.07 g, yield: quantitative).