Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)[C:32]([O:34]CC)=[CH2:33])CCC>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.O1CCOCC1>[OH:11][C:9]1[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:6]2=[N:7][C:2]([C:32](=[O:34])[CH3:33])=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
An oven-dried scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), and (Ph3P)4Pd (0.07 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5 min, and anhydous dioxane (13 volume equivalents), triethylamine (3.0 equiv), and tributyl(1-ethoxyvinyl)stannane (1.5 equiv) were added by syringe. The resulting mixture was heated to 80° C. overnight. The reaction was quenched with 1 N KHSO4 and stirred for 30 min. The mixture was then diluted with EtOAc, washed twice with NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 10%-66% EtOAc/Hexanes) provided the title compound (33%) as a white solid. LCMS m/z (APCI)=283.1 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)CC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added t-butylacetyl chloride (0.31 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3,3-dimethyl-butyramide as a light yellow solid (120 mg, 22% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.74 min (98.4%); mp, 212-214° C.; 1HNMR (DMSO-d6) 0.96 (s, 9H, 3CH3), 2.08 (s, 2H, CH2Me3), 2.12-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.68-4.85 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.34-7.76 (m, 3H, Ar), 8.11 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.76, 23.28, 29.69, 30.47, 30.58, 41.43, 48.76, 56.47, 117.65, 124.64, 125.42, 133.77, 141.19, 148.42, 154.75, 160.93, 169.51, 170.97, 172.60. LCMS MH=399; Anal Calcd For C21H26N4O4+0.1H2O: C, 63.02; H, 6.60; N, 14.00. Found: C, 62.86; H, 6.70; N, 13.92.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li+].[Cl-].C[CH2:15][O:16]C(C)=O>FC(F)(F)C(O)=O.CO.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]2[C:15](=[O:16])[O:10][CH2:9][C:4]=2[C:3]=1[CH3:11]
Reactant: Cc1cc(Br)c(C)c(CO)c1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)c(C)c2c1C(=O)OC2
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-2,5-dimethylphenyl)methanol (1.6 g, 7.4 mmol) in trifluoroacetic acid (20 mL) was added Tl(OOCF3)3 (4 g, 7.4 mmol) at r.t, then the reaction was stirred at r.t overnight under N2. The mixture was concentrated under pressure. The residue solids, LiCl (0.6 g, 14.9 mmol), MgO (0.6 g, 14.9 mmol) and PdCl2 (0.13 g, 0.74 mmol) in MeOH were stirred under CO at 1 Mpa over night. EtOAc was added to the mixture and filtered. The organic phase was concentrated to afford 5-bromo-4,7-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [C:1]([NH:8][O:9][CH2:10][CH:11]=[CH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:16][CH2:17][CH3:18]>C1COCC1>[C:1]([N:8]([CH2:16][CH2:17][CH3:18])[O:9][CH2:10][CH:11]=[CH2:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCCI
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCON(CCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Boc-O-allylhydroxylamine (6.5 g) from the above procedure was dissolved in dry THF (25 mL) and the solution cooled to 0° C. in an ice bath. Sodium hydride (1.5 g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min at 0° C. 1-Iodopropane (3.8 mL) was added dropwise to the mixture. The reaction was stirred at 0° C. for 1 hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×50 mL), saturated sodium bicarbonate solution (3×50 mL), 1N phosphoric acid (3×50 mL), and brine (1×50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1O

Procedure:
0.75 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 12 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(3-hydroxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 205°-207° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C3CC3)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C2CC2)c1
Yield: 68.7 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.132 g, 0.230 mmol) was dissolved in DCM (3 mL) and treated with TFA (3 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.0705 g, 0.158 mmol, 68.8% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.26 (br. s., 1H), 7.78 (s, 1H), 7.31-7.55 (m, 2H), 7.27 (br. s., 1H), 7.09 (s, 2H), 4.53 (d, J=1.39 Hz, 2H), 1.91-2.07 (m, 1H), 0.99 (m, 2H), 0.77 (m, 2H). LC-MS (ES−) m/z 443.18, 445.11 [M−1]. LC-MS (ES+) m/z 445.07, 447.08 [M+H].
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:7])=[O:6]
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NS(=O)(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-isopropyl-2-nitrobenzenesulfonamide (774 mg) in methanol (50 mL) was added Pd/C (10% Pd in carbon, 150 mg, 19 wt %) under argon protection. A hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product 2-amino-N-isopropylbenzenesulfonamide (quantitative yield).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: Nc1ccc(-c2ccccc2C(F)(F)F)nc1
Yield: 59 %

Procedure:
Obtained (2.05 g, yield 59%) following the procedure described in Intermediate 27, starting with 6-bromopyridin-3-amine, 2-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and pyrrolidine in tetrahydrofuran are reacted to give 8-chloro-1-(pyrrolidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[NH:27][C:26]5[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:25]=5[N:24]=4)[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].ClC1N=C(C2C=CC(CN3CCC(N4C5C=CC=CC=5NC4=O)CC3)=CC=2)C(C2C=CC=CC=2)=CC=1C#N.[C:77]([O:81][CH3:82])(=[O:80])[CH2:78][OH:79].C[O-].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[N:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([C:23]5[NH:27][C:26]6[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:25]=6[N:24]=5)[CH2:19][CH2:18]4)=[CH:14][CH:15]=3)=[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:6]=2)[O:79][C:78]=1[C:77]([O:81][CH3:82])=[O:80]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)nc1Cl
Reactant: COC(=O)CO
Agent: C[O-]
Agent: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2nc(-c3ccc(CN4CCC(c5nc6ccc(F)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cc2c1N

Procedure:
The solution of 2-chloro-6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (3-1, synthesis made in a similar manner as shown in Scheme 1, compound 1-6; 0.026 g, 0.05 mmol), methyl glycolate (0.01 g, 0.11 mmol) and potassium methoxide (0.009 mg, 0.11 mmol) in DMF (1 mL) was heated to 70° C. for 1 h. The mixture was purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) to give Methyl 3-amino-6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylfuro[2,3-b]pyridine-2-carboxylate (3-2). LRMS m/z (M+H) Calcd: 576.6, found: 576.2.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: Nc1ccc(Oc2ncc(Cl)cn2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Oc2ncc(Cl)cn2)cc1
Reaction time: 0.08 h

Procedure:
2-(4-Aminophenoxy)-5-chloropyrimidine (20 g), was dissolved in acetic acid (100 ml), and acetic anhydride (20 ml) was added to the solution. After standing for a period of 5 minutes the solution was heated on a steam bath and hot water (100 ml) was slowly added. On cooling the product crystallised and was collected and dried. Yield 20 g, m.p. 202° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:17](I)([CH3:19])[CH3:18]>CC(C)=O.[Ag]=O>[CH:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: CC(C)I
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CC(C)N1CCCC(c2cccc(C(F)(F)F)c2)C1
Reaction time: 24 h

Procedure:
3.4 g of silver oxide were added to a solution of 9.2 g of 3-(m-trifluoromethylphenyl)-piperidine in 45 ml of acetone and after 61/2 hours of stirring 1.1 g of silver oxide and 4.9 ml of isopropyl iodide were added. The mixture was stirred for 24 hours and was filtered. The filtrate was evaporated to dryness to obtain 10.4 g of N-isopropyl-3-(m-trifluoromethylphenyl)-piperidine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O.O>CN(C)C=O>[F:36][C:35]([F:38])([F:37])[CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a stirred solution of tert-butyl 4-(3-hydroxyphenoxy)piperidine-1-carboxylate (2.00 g, 6.82 mmol) and cesium carbonate (4.44 g, 13.6 mmol) in N,N-dimethylformamide (25 mL) was added 2,2,2-trifluoroethyl trifluoromethane-sulfonate (1.74 g, 7.50 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.42 g (95%) of the title compound as colorless oil.
Reaction SMILES: OC(C1C=C2C(=CC=1)C=C(C(OC)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[OH:44][C:45]([C:73]1[CH:74]=[C:75]2[C:80](=[CH:81][CH:82]=1)[CH:79]=[C:78]([C:83](O)=[O:84])[CH:77]=[CH:76]2)([C:49]1[N:50]=[CH:51][N:52](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:53]=1)[CH:46]([CH3:48])[CH3:47].Cl.[CH:87]([O:90][NH2:91])([CH3:89])[CH3:88]>>[OH:44][C:45]([C:73]1[CH:74]=[C:75]2[C:76](=[CH:81][CH:82]=1)[CH:77]=[C:78]([C:83]([NH:91][O:90][CH:87]([CH3:89])[CH3:88])=[O:84])[CH:79]=[CH:80]2)([C:49]1[N:50]=[CH:51][NH:52][CH:53]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)ON
Agent: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: Cl
Product: CC(C)ONC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.77 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with O-isopropylhydroxylamine hydrochloride (420 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.46 g) as a pale yellow powder.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13](S(C)(=O)=O)=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13]([CH2:4][CH3:5])=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(I)cc1
Reactant: CC[Zn]CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Add dropwise diethylzinc (1.0M in hexanes, 16 mmol) to a solution of 3-(4-iodophenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (2.78 mmol) in 15 mL of anhydrous CH2Cl2 and stir under nitrogen at room temperature for 5 days. Cool to 0° C. and carefully quench with ice followed by 10 mL of saturated NH4Cl. Filter the mixture through Celite and rinse the filter pad with 100 mL of CH2Cl2. Wash the combined organic layers with brine (1×20 mL), dry over Na2SO4, filter, and evaporate. Chromatograph (hexane:ethyl acetate 3:1) over silca gel to provide the title compound: MS (ES+, m/e): 412 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:41][CH2:40]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 67.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (536 mg, 1.24 mmol, 67%) was obtained.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:36]1[C:40]2[C:41]([CH:45]=O)=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][CH2:37]1>C1COCC1.O>[O:36]1[C:40]2[C:41]([CH:45]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][CH2:37]1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2c1OCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC=Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (617 mg, 1.5 mmol) in THF (20 mL) was added NaHMDS (1.5 mL, 3.0 mmol) at −20° C., and the reaction was stirred for 20 min. 2,3-Dihydro-1-benzofuran-7-carbaldehyde (200 mg, 1.4 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4), and concentrated to give the crude title compound as a yellow solid. [M+H] Calc'd for C12H12O3, 205. Found, 205.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]#[N:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]#[N:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1c(N)ccc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1c(NC(=O)c2ccccc2)ccc2ccccc12

Procedure:
3.0 g (17.8 millimoles) of 2-aminonaphthalene-1-carbonitrile (Chem. Pharm. Bull 33 (4) (1985), 1360-1366) were stirred with 2.5 g (18.1 millimoles) of benzoyl chloride and 4 ml of triethylamine in 100 ml of toluene for 15 hours at 80° C. After the end of the reaction, the product was filtered off and dried. 1.5 g (31% of theory) of the title compound of melting point 205° C. (active ingredient example 1008) were obtained in this manner.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: Cc1ccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure I′ above, and using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.