Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:7]>C(#N)C>[N:3]([C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:7])=[C:2]=[S:1]
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N=C=S)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Potassium thiocyanate (1.08 g) is added to a solution of methyl 4-chlorocarbonylbenzoate (2 g) in acetonitrile (30 ml). After stirring for 1 hour at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The solid obtained is purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1) in order to produce the expected compound (2.1 g; 95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1)[CH2:20][CH2:21][CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][O:16][C:26]1[N:25]=[N:24][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:28]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:33][CH:34]=2)[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nnc(OCC[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.87 mmol, 0.20 g) in DMF (1.0 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (2.61 mmol, 0.104 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.435 mmol, 0.15 g) in DMF (1.0 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 12 hour. The reaction was poured into a mixture of water (10 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using ethyl acetate/hexanes gradient to give (R)-2-{2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1.[CH3:22]C(C)([O-])C.[K+].CI.CCOC(C)=O>O1CCCC1.CCCCCCC>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:16][CH2:17][CH:18]([O:21][CH3:22])[CH2:19][CH2:20]3)[C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
6′-(3-Fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 64, 1.94 g, 6.64 mmol) was dissolved in tetrahydrofuran (35 mL) under argon and cooled to 0° C. Potassium tert-butoxide (2.23 g, 19.9 mmol) was added portion wise and the mixture was stirred at 0° C. for 15 min. Methyl iodide (0.83 mL, 13.3 mmol) was added. The cooling bath was removed, and the mixture was stirred at r.t. overnight. Water (200 mL) was added and the resulting solution was partitioned between additional water (200 mL) and EtOAc (400 mL). The organic phases was dried over MgSO4 and concentrated in vacuo. The product was isolated using flash chromatography using a gradient of EtOAc (0-50%) in heptane to give 0.611 g (30% yield) of the title compound: MS (ES+) m/z 307 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([F:45])=[C:20]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F-].[Cs+].[NH2:48][C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1.O>COCCOC.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>[NH2:48][C:49]1[CH:54]=[C:53]([C:2]2[S:3][C:4]([C:13]([C:15]3[CH:23]=[C:22]4[C:18]([C:19]([F:45])=[C:20]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:21]4[CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:17][CH:16]=3)=[O:14])=[CH:5][C:6]=2[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:52]=[CH:51][CH:50]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(N)c1
Yield: 76.4 %

Procedure:
A mixture of 6 (40 mg, 0.058 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), CsF (27 mg, 0.18 mmol), 3-aminophenylboronic acid (12 mg, 0.088 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 minutes and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 7 as a yellow amorphous solid (31 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.78-7.67 (m, 7H), 7.51-7.41 (m, 5H), 7.23 (t, J=8.0 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.85 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 4.26 (t, J=7.0 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.82 (brs, 2H), 3.70 (s, 2H), 3.48 (t, J=6.8 Hz, 2H), 1.66-1.60 (m, 2H), 1.48-1.45 (m, 2H), and 1.25 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.13, 171.26, 168.49, 149.66, 147.09, 143.16, 141.68, 140.71, 137.58, 134.19, 132.51, 132.44, 132.38, 132.14, 130.54, 130.05, 129.97, 129.54, 129.15, 129.06, 128.94, 128.58, 127.31, 127.10, 123.47, 121.43, 120.02, 119.86, 119.71, 116.81, 115.88, 115.69, 112.56, 61.31, 43.61, 37.25, 34.77, 27.36, 25.77, and 14.45; 19F NMR (376 MHZ, CDCl3) δ −174.49.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[C:6]=1[CH3:29].COC(=O)CC1C2C(=NC=CC=2)NC=1C.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.BrCC1C=CC(S(C)(=O)=O)=CC=1C(F)(F)F>CN(C=O)C>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]2[CH3:29])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice-cooled solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (400 ml) under an inert atmosphere of Argon is added dropwise, BEMP (18.1 ml, 62.8 mmol) over two minutes. After stirring at 10° C. for 40 minutes, the resulting solution is treated dropwise with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (23.8 g, 75.4 mmol) and allowed to warm to room temperature while stirring overnight. The reaction is concentrated in vacuo with toluene azeotroping and the resulting oil is partitioned between water (400 ml) and DCM (500 ml) and extracted with DCM (500 ml). The organic portions are combined and washed with water (2×200 ml). The resulting suspension is filtered and concentrated in vacuo with toluene azeotroping. The crude is purified by chromatography on silica eluting with iso-hexane/acetone (16:4) to yield the titled product. (MH+ 441)
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 8.7 %

Procedure:
Pd(PPh3)4 (28 mg, 0.073 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (28 mg, 0.073 mmol) in toluene (4.4 mL), Na2CO3 (2 N, 2.2 mL) and 4-cyanophenylboronic acid (12.9 mg, 0.088 mmol). The mixture was refluxed under Ar for 3˜5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.58 mg, 9%). 1H-NMR (CDCl3): 0.92 (m, 1H), 1.07 (m, 1H), 1.75 (s, 3H), 4.32 (d, 1H), 5.62 (d, 1H), 5.82-5.98 (m, 5H), 6.06 (m, 2H), 6.15 (m, 2H), 6.47 (d, 1H), 6.46 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:34])=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH2:44]([N:47]1[C:51]([CH2:52][S:53]([C:55]2[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=2)=[O:54])=[CH:50][N:49]=[CH:48]1)[CH2:45][CH3:46]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:34])=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:59][C:58]4[CH:57]=[CH:56][C:55]([S:53]([CH2:52][C:51]5[N:47]([CH2:44][CH2:45][CH3:46])[CH:48]=[N:49][CH:50]=5)=[O:54])=[CH:61][CH:60]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)O)=C3)cc1
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)=C3)cc1
Reaction time: 0.5 h

Procedure:
(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate monohydrate (660 mg) was dissolved in ethyl acetate (5 ml) and 1N hydrochloric acid (2.87 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (2.87 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) three times. The organic layers were combined and washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, after which the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (380 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, and then thionyl chloride (0.071 ml) was added, and the mixture was stirred under nitrogen atmosphere for 30 minutes. The resulting solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and triethylamine (1.35 ml) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 3 hours, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous acetic acid solution twice, with aqueous saturated sodium bicarbonate solution twice, and with saturated brine once, after which the resultant was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resultant was separated and purified with a basic silica gel column chromatography (hexane:ethyl acetate=4:1→ethyl acetate) to give (−)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-9-methyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (266 mg) (Compound 24) as a yellow amorphous material.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH:24](N1CCOCC1)=[O:25].[Cl-].[NH4+]>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[O:14][C:15]3[C:7]([CH:24]=[O:25])=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)=[CH:17][CH:18]=1
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(-c2cc3cccc(Br)c3o2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cccc(C=O)c3o2)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
83 ml of butyllithium were added at -70° C. to a mixture of 36.4 g of the product of Step B and 100 ml of tetrahydrofuran and the mixture was stirred for one hour at -60° C., 24.2 ml of N-formyl morpholine in 50 ml of tetrahydrofuran were added and the reaction mixture was stirred for 16 hours at -60° C. Ammonium chloride was added and the two phases were decanted. Extraction was carried out with ethyl acetate, followed by drying and concentrating to obtain 35.12 g of product which was purified by chromatography on silica, eluting with a hexane - ethyl acetate mixture (9-1) to obtain 13.8 g of the desired product.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:16]1(C(OC(C)(C)C)=O)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[I-].[Na+].C(N(CC)CC)C.FC(F)(F)C(O)=O>O1CCCC1>[C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
N-tert-Butyl-3-(chloromethyl)benzamide (14.71 g, 65.2 mmol), tert-butyl piperazine-1-carboxylate (12.14 g, 65.2 mmol), sodium iodide (1.95 g, 13.0 mmol), triethylamine (27.3 mL, 195.5 mmol) and tetrahydrofuran (125 mL) were stirred together at room temperature for 18 hours. The reaction was then concentrated under vacuum and the residue dissolved in ethyl acetate. The organic mixture was washed consecutively with saturated aqueous sodium hydrogen carbonate solution, water (×2) and brine then concentrated under vacuum. The residue was dissolved in dichloromethane (100 mL), treated with trifluoroacetic acid (25.0 mL, 326.0 mmol) and stirred at 60° C. for 2.5 hours. The reaction was concentrated under vacuum and purified by strong cation exchange (SCX) chromatography, eluting macroporous polystyrene sulfonic acid with 2M ammonia in methanol. The resulting solution was concentrated under vacuum to give the title compound (12.8 g) as a white solid.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[C:26]2[C:21](=[C:22]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:28](=[O:29])[CH:27]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[CH3:31])=[CH:10][C:9]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(N2CCCCCC2)c(F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(N2CCCCCC2)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 406 (M+H)+; MS (ESI−) m/z 404 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (m, 7H), 1.72 (m, 4H), 3.32 (m, 4H), 3.65 (s, 2H), 4.18 (q, J 7.1, 1H), 6.86 (m, 3H), 7.58 (m, 2H), 7.74 (m, 1H), 8.13 (m, 2H), 8.52 (d, J 7.8, 1H), 9.30 (s, 1H); Anal. Calcd for C25H28FN3O+3.25HCl: C, 57.30; H, 6.01. Found: C, 57.26; H, 5.98.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C@H:18]([OH:23])[CH2:19][C:20](=[O:22])[CH3:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:35]2[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=2)[N:29]=[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])[N:27]=1.C(N(CC)CC)C>[Pd].CO>[OH:23][C@H:18]([CH2:19][C:20](=[O:22])[CH3:21])[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:35]3[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[N:27]=2)[CH2:16][CH2:15]1)=[O:24]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of 4-((R)-2-hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylic acid benzyl ester (0.13 g, 0.39 mmol) and MeOH (4 mL) was stirred with 10 mg of Pd/C (10% wt Pd on carbon) under H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent, the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.11 g, 0.39 mmol) and triethylamine (0.11 mL, 0.78 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1,4-dione as a yellow solid (91 mg, 54%). LC/MS: m/z 435.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))yl)piperazin-1-yl)pentan-1,4-dione as a yellow solid (91 mg, 54%). LC/MS: m/z 435.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15].[CH2:17]([O:19][C:20](=O)[O:21]CC)[CH3:18].[H-].[Na+].CC(O)=O>C1(C)C=CC=CC=1.O>[CH2:17]([O:19][C:20](=[O:21])[CH2:15][C:14](=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[CH3:18]
Reactant: CC(=O)c1ccccc1OCC1CCCO1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccccc1OCC1CCCO1
Yield: 63.3 %

Procedure:
A mixture of 1-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-ethanone (2.22 g, 0.01 mol) and diethylcarbonat (10 mL, 0.083 mol) in anhydrous toluene (20 mL) was added dropwise to a suspension NaH (1.0 g, 0.025 mol) in anhydrous toluene (20 mL). After addition, the mixture refluxed for 2 h, cooled and poured slowly into a solution AcOH (3 mL) and water (50 mL). After separated the organic layer, the aqueous layer was extracted with ethyl acetate (2×50 mL). Organic layers were combined, washed with water (20 mL), then dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (eluent hexane-ethylacetate, 1:5) to obtain 1.85 g (64%) 3-oxo-3-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-propionic acid ethyl ester as yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:10])[CH2:5][CH2:4]1.[Sn](Cl)Cl.O.[OH-].[Na+]>C(O)C.O1CCCC1>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=3)=[O:25])=[C:12]([NH:11][C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[CH3:34])[CH2:4][CH2:5]3)=[O:10])[C:16]=2[CH:17]=1
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc([N+](=O)[O-])cc23)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-nitro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (3.00 g) obtained in Example 18 is suspended in ethanol (100 ml), and thereto are added tin(II) chloride (anhydrous) (7.02 g) and water (1.0 ml). The mixture is heated under reflux for 7 hours, and allowed to stand for cooling. To the reaction solution are added 10% aqueous sodium hydroxide solution (30 ml) and tetrahydrofuran (200 ml), and the mixture is stirred at room temperature for one hour. The insoluble materials are filtered on celite, and the filtrate is concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then chloroform/ethyl acetate=1/1). The resulting residue is suspended in ethyl acetate/n-hexane, and the precipitates are collected by filtration and dried to give trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (1.43 g). This product (35 mg) is dissolved in ethanol, and treated with 4N hydrogen chloride/ethyl acetate to give the title compound (43 mg).
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C:13](=O)[CH2:12]2.N12CCN(CC1)CC2.S([O-])([O-])(=O)=O.[Mg+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:13]3[CH:14]4[CH2:17][CH2:18][N:11]([C:12]=3[C:2]=2[CH:8]=1)[CH2:16][CH2:15]4
Reactant: O=C1CN2CCC1CC2
Reactant: Cc1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Product: Cc1ccc2[nH]c3c(c2c1)N1CCC3CC1

Procedure:
2-Iodo-4-methylaniline (2.0 g, 8.58 mmol; prepared as described in J. Org. Chem. 1999, 64, 9650), quinuclidin-3-one hydrochloride (2.36 g, 14.6 mmol; Aldrich), palladium(II) acetate (145 mg, 0.646 mmol; Aldrich), 1,4-diazabicyclo[2.2.2]octane (DABCO; 3.47 g, 30.9 mmol; Aldrich) and magnesium sulfate (1.65 g, 13.7 mmol) were processed as described in Example 205A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 1.52-1.62 (m, 2H), 1.92-2.05 (m, 2H), 2.39 (s, 3H), 2.55-2.69 (m, 2H), 3.22-3.29 (m, 2H), 3.40 (quintet, J=2.9 Hz, 1H), 6.85 (dd, J=8.2, 1.5 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.34 (s, 1H); MS (APCI) m/z 213 (M+H)+.