Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].Cl[C:11](OC)=O.C(=O)([O-])O.[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:11])[CH3:2]
Reactant: CCN(CC)CCCN
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNC
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwise methyl chloroformate (5.15 ml) while stirring in an ice bath. After stirring at room temperature for 30 min, a saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the reaction mixture, and liquid-liquid separation was carried out. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved again in ethyl acetate (200 ml), dried over potassium carbonate, and concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189). The residue was dissolved in tetrahydrofuran (200 ml), and lithium aluminum hydride (2.00 g) was gradually added thereto while stirring in an ice bath. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min, then at 65° C. for 1.5 hr. The reaction mixture was cooled in an ice bath, water (2.0 ml), a 5N aqueous solution of sodium hydroxide (2.0 ml) and water (10.0 ml) were added thereto in this order, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to provide the titled compound as a pale yellow oil (9.2 g, 72%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10](=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([OH:13])=[CH:15][CH:16]=2)[C:11]#[N:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#CC(=Cc1ccc(O)cc1)S(=O)(=O)c1ccccc1
Yield: 66 %

Procedure:
Phenylsulphonyl acetonitrile (2.0 g, 11.04 mmol) was mixed with 4-hydroxybenzaldehyde (1.35 g, 11.04 mmol) in DMF (10 mL) and toluene (20 mL). The mixture was refluxed for 3 hours and subsequently evaporated to dryness in vacuo. The residue was treated with diethyl ether and toluene. The solid formed was filtered to afford 2.08 g (66%) of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:52]=1[CH2:61][C:62]([OH:64])=O>>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:51]([O:50][CH3:49])[C:52]=1[CH2:61][C:62]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:64]
Reactant: COc1cc(OC)c(CC(=O)O)c(OC)c1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: COc1cc(OC)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(OC)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,4,6-trimethoxyphenylacetic acid, mp 159°-163° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:25])=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19]3=[O:24])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=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]>[CH3:23][N:20]1[CH2:21][CH2:22][N:18]([C:16]([NH:15][C:12]2[CH:11]=[C:10]([CH3:25])[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:30]4[CH:31]=[C:27]([CH3:26])[N:28]=[CH:29]4)[CH:7]=3)=[CH:14][N:13]=2)=[O:17])[C:19]1=[O:24]
Reactant: Cc1cc(NC(=O)N2CCN(C)C2=O)ncc1Oc1ccnc(Cl)c1
Reactant: Cc1c[nH]cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(Oc3cnc(NC(=O)N4CCN(C)C4=O)cc3C)ccn2)cn1
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A solution of Pd2(dba)3 (10.12 mg, 0.011 mmol) and Me4t-BuXPhos (0.012 g, 0.025 mmol) in toluene (0.2 mL) and dioxane (0.4 mL) was heated at 120° C. for 3 min, cooled to RT, added to a degassed suspension of N-(5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-yl)-3-methyl-2-oxoimidazolidine-1-carboxamide (0.1 g, 0.276 mmol), 4-methyl imidazole (0.030 g, 0.359 mmol) and K3PO4 (0.117 g, 0.553 mmol) in toluene (0.4 mL) and dioxane (0.8 mL) and heated at 110° C. overnight. The mixture was treated with additional catalyst (synthesized from Pd2(dba)3 (10.12 mg, 0.011 mmol) and Me4t-BuXPhos (0.012 g, 0.025 mmol) in toluene (0.2 mL) and dioxane (0.4 mL) as above) and heated at 110° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (5×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM). The material was treated with MeCN, heated to reflux, cooled to RT and the resulting solid collected via filtration and dried to afford 3-methyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (20 mg, 17%). 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1 H), 8.39 (d, J=1.4 Hz, 1 H), 8.30 (d, J=5.8 Hz, 1 H), 8.13 (s, 1 H), 8.02 (s, 1 H), 7.64 (t, J=1.3 Hz, 1 H), 7.33 (d, J=2.2 Hz, 1 H), 6.73 (dd, J=5.8, 2.2 Hz, 1 H), 3.79-3.78 (m, 2 H), 3.46-3.44 (m, 2 H), 2.80 (s, 3 H), 2.15 (s, 3 H), 2.13 (s, 3H); MS (ESI) m/z: 408.2 (M+H+).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:52][OH:53]>CC(N(C)C)=O>[CH2:54]([C@H:51]([NH:50][C:26](=[O:28])[C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1)[CH2:52][OH:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
In a microwave vial containing 3 eq. of PS-DCC, 4-(pyridin-4-yl)benzoic acid (20 mg, 0.1 mmol) was added dissolved in DMA (1.0 ml). Then a solution of HOBT (14 mg, 0.1 mmol) dissolved in DMA (0.3 ml) was added followed by the addition of DIEA (36 μl, 0.2 mmol) dissolved in DMA (0.3 ml) and the addition of (S)-2-amino-3-phenylpropan-1-ol (17 mg, 0.11 mmol) dissolved in DMA (0.6 ml). The mixture was heated in the microwave to 100° C. for 600 seconds. The reaction was filtered through Si-Carbonate, 6 ml-1 g supplied by Silicycle chemical Division and transferred to 20 ml vials. The reaction was checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (TFA method). Product was characterized by 1H NMR, MS and LC/MS.
Reaction SMILES: [Br:1][C:2]1[C:23](C(O)=O)=[C:5]2[CH:6]=[C:7]([C:10](=[O:22])[N:11]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:9][N:4]2[N:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:23]=[C:5]2[CH:6]=[C:7]([C:10]([N:11]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[O:22])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(Br)c(C(=O)O)c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(Br)cc2c1
Reaction time: 0.18 h
Yield: 70.7 %

Procedure:
A solution of 2-bromo-5-(diisopentylcarbamoyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.285 g, 0.672 mmol) in diphenyl ether (6 ml) was heated to 210° C. for 9 hours. The mixture was allowed to cool, loaded on a silica gel pad, rinsed with diethyl ether (10 mL) and dried thoroughly under vacuum. The dried silica gel pad was then connected to a 24 g silica gel ISCO Gold cartridge and eluted with hexanes for 3 min then 0% to 100% ethyl acetate over 11 min. Concentration of the desired fractions afforded 2-bromo-N,N-diisopentylpyrazolo[1,5-a]pyridine-5-carboxamide (0.19 g, 0.475 mmol, 70.7% yield) as a yellow oil. LCMS m/z 380.1, 382.1 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:16][CH3:17])=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[Li+].[OH-].Cl>C1COCC1>[CH3:17][O:16][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:18])=[O:2])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=1
Reactant: COC(=O)C=Cc1cnc(OC)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 3-(6-methoxy-4-trifluoromethylpyridin-3-yl)-acrylic acid methyl ester (trans isomer, 59 mg, 0.23 mmol) in THF (2 mL) was added 1 N LiOH (2 mL). The mixture was stirred at room temperature for 2 hours, acidified to pH 5 with 3 N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylic acid (50 mg, 89.6%) as a solid.
Reaction SMILES: Cl.[C:2]([N:6]1[CH2:10][CH2:9][CH:8](O)[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][CH:8]1[CH2:9][CH2:10][N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:7]1
Reactant: CC(C)(C)N1CCC(O)C1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)N1CCC(Cl)C1
Yield: 63.1 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 1-t-butyl-3-pyrrolidinol (146 g, 1.02 mol) in chloroform (1.01) until the reaction mixture became acidic. A solution of thionyl chloride (1.55 g, 1.3 mol) was added dropwise with warming. After the addition was completed, the reaction mixture was stirred at reflux temperature for 18 h. The chloroform and excess thionyl chloride was removed on a rotary evaporator. Cracked ice and water was added to the residue and the mixture basified with 25% sodium hydroxide solution. The mixture was extracted with chloroform, and the extract washed with brine solution. The extract was dried (Na2SO4), concentrated and distilled at 75° C./15 mm to obtain 104 g (63%) of the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]([N:29]1[CH2:34][CH2:33][CH:32]([S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH2:31][CH2:30]1)[CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:20][N:19]=1)=[O:17]>C(Cl)Cl>[O:12]=[C:13]([N:29]1[CH2:30][CH2:31][CH:32]([S:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:44])([F:43])[F:45])=[O:9])[CH2:33][CH2:34]1)[CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:20][N:19]=1)=[O:17]
Reactant: O=C(NCC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCC(S(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
m-Chloroperbenzoic acid (18.5 mg, 0.1 mmol) was added to a cold (0-4° C.) solution of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylsulfanyl)-piperidin-1-yl]-ethyl}-amide (50 mg, 0.1 mmol) in DCM (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated. Purification by column chromatography (using 60-120 silica gel and 0.6% MeOH in CHCl3 as eluent) afforded 30 mg (58.35% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzenesulfinyl)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 505.15, 95.9%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.2-7.9 (m, 4H), 7.9-7.8 (m, 3H), 7.6-7.4 (t, 2H), 7.4 (t, 1H), 7.1 (s, 1H), 4.5 (d, 1H), 4.2 (d, 2H), 4.0 (d, 1H), 3.1 (m, 2H), 2.8-2.5 (m, 2H), 1.9 (d, 1H), 1.7 (dd, 1H), δ 1.6-1.4 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=O)=[CH:6][CH:5]=1.[CH3:14][C:15]1([CH3:22])[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH2:21]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:21][CH2:20][CH:16]2[CH2:17][CH2:18][CH2:19][C:15]2([CH3:22])[CH3:14])=[O:10])=[CH:11][CH:12]=1
Reactant: CC1(C)CCCC1CN
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Product: COC(=O)c1ccc(C(=O)NCC2CCCC2(C)C)cc1

Procedure:
The title compound was prepared from monomethylterephthalate and 2,2-dimethylcyclopentylmethyl amine (title B compound of Example 1) in a manner as described for the title A compound of Example 24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7](Cl)[C:6]=2[CH:16]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7]([O:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:6]=2[CH:16]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: COc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Oc2ccc(OC)cc2)c2cc(Br)ccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g) with sodium hydride (0.8 g of 60% in oil) and 4-methoxyphenol (0.24 g) in dry dimethylformamide (5 ml) was stirred at room temperature overnight under nitrogen. The mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The extracts were washed with sodium hydroxide, brine, dried and evaporated under reduced pressure. The residue was triturated with light petroleum (b.p. 40-60° C.) to give 6-bromo-4-(4-methoxyphenoxy)-3-propyl-2H-1-benzopyran-2-one, m.p. 104-6° C. (compound 20).
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH:37]3[CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[CH:37]1([C:33]2[CH:34]=[C:35]([CH3:36])[C:30]([N:27]3[CH2:26][CH2:25][N:24]([C:22]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][C:17]5=[O:21])=[CH:15][C:10]=4[C:9]([N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[O:40])=[O:23])[CH2:29][CH2:28]3)=[N:31][CH:32]=2)[CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N2CCOCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 814 and morpholine (38 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (20 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16](B(O)O)=[CH:15][C:14]=3[CH:21]=2)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:38]=[CH:37][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29]2)=[CH:25][C:24]=1[F:39]>>[F:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[C:16]1[O:17][C:13]2[CH:12]=[CH:11][C:10]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([CH3:9])[CH3:8])=[CH:21][C:14]=2[CH:15]=1)[CH2:27][N:28]1[CH2:29][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31]1
Reactant: CC(C)(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(C(C)(C)c5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B2, Step 2 and general procedure F from 5-(2-phenylpropan-2-yl)benzofuran-2-ylboronic acid and ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate to give ethyl 1-(3-fluoro-4-(5-(2-phenylpropan-2-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylate as a yellow foam. MS (ESI) m/z: Calculated: 471.2; Observed: 472 (M++1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[CH:19]=1)=[O:12].N1C=CC=CC=1>C(Cl)Cl>[CH3:34][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=2)[CH:19]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulphonyl chloride (0.46 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-aminobenzamide, pyridine (0.56 ml) and methylene chloride (30 ml) and the resultant mixture was stirred at ambient temperature for 48 hours. The precipitate was isolated, washed in turn with methylene chloride and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (1.64 g); m.p. 239-240° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.03 (s, 9H), 7.24 (m, 2H), 7.45 (m, 5H), 7.59 (m, 1H), 7.71 (m, 1H), 7.27 (m, 1H), 7.77 (d, 1H), 7.82 (d, 1H), 9.94 (br s, 1H), 10.24 (br s, 1H); Mass Spectrum: M−H− 465.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.C(N(CC)C(C1C=CC2C(=O)C3C(OC=2C=1)=CC=CC=3)=O)C.[F:41][C:42]([F:55])([F:54])[C:43]([N:45]1[CH:50]2[CH2:51][CH2:52][CH:46]1[CH2:47][C:48](=O)[CH2:49]2)=[O:44]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:48]3[CH2:47][CH:46]4[N:45]([C:43](=[O:44])[C:42]([F:54])([F:41])[F:55])[CH:50]([CH2:51][CH2:52]4)[CH2:49]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: O=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: COc1cccc2c(=O)c3ccc(Br)cc3oc12
Agent: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Product: COc1cccc2c1Oc1cc(Br)ccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 7, substituting 3-bromo-5-methoxy-xanthen-9-one, 3k for 9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 6a and 8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]octan-3-one for N-carbethoxynortropinone, the title compound 1-[3-(3-bromo-5-methoxy-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 4k was obtained. MS m/z (MH+) 467.7, 469.7.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=4)[C:19]([S:30][CH3:31])=[CH:18]3)=[N:15][CH:16]=2)[CH:6]=1>C1COCC1.O>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[N:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=4)[C:19]([S:30][CH3:31])=[CH:18]3)=[N:13][CH:12]=2)[CH:6]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccn4)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cn(-c2ncc(-c3cc(C)ccn3)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.27 g, 6.4 mmol) was added to an ice-cooled suspension of the methyl ester 269a) (1.0 g, 2.56 mmol) in THF/water (1:1, 50 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum, and the residue was dissolved in water (20 mL) and washed with dichloromethane (2×20 mL). The aqueous phase was acidified with sodium hydrogen sulfate and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. White solid. Yield: 0.9 g (93% of theory)
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[N:21]1([S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[C:10]3=[O:11])(=[O:14])=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C1=O
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a cold solution of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride (2.00 g, 8.14 mmol) in a 1:1 mixture of THF: CHCl3 (96 mL) was added drop-wise via syringe pump over a period of 1 hr a solution of pyrrolidine (0.885 mL, 10.6 mmol) and N,N-diisopropylethyl amine (2.84 mL, 16.3 mmol, 2 eq) in chloroform (16 mL) under a dry N2 atmosphere with cooling in an ice bath. After stirring for 1 h., the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with 80/20 CH2Cl2/EtOAc to give the title compound as a greenish-yellow solid (0.88 g, 39% yield). NMR (300 Mz, DMSO-d6): consistent. MS: (ES−) m/z 279 [M−H].
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:29]1([CH2:35][S:36][CH:37]([C:41](O)=[O:42])[C:38](O)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[OH:42][C:41]1[CH:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)[O:3][C:38](=[O:39])[C:37]=1[S:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc3ccccc3c2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 2-acetyl naphthalene (1.97 g, 11.6 mmol), lithium bis(trimethylsilyl)amide (2.13 g, 12.76 mmol), chlorotrimethylsilane (1.61 mL, 12.76 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thio]-propanedioic acid (2.90 g, 10.5 mmol). m.p. dec. 203° C.; 1H NMR (250 MHz, DMSO-d6) δ 4.04 (s, 2 H), 6.89 (s, 1 H), 7.23 (in, 5 H), 7.61 (m, 2 H), 7.84 (d, 2 H), 8.05 (m, 3 H), 8.43 (s, 1 H), 11.95 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[O:18][N:17]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: Cc1noc(C)c1-c1nc(Cn2c(C)cc3c(Cl)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.58 (d, J=8.5 Hz, 1 H), 5.81 (s, 2 H), 3.30 (s, 3 H), 2.66 (s, 3 H), 2.39 (s, 3 H); MS (ES) m/z 368 (M+1).