Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[F:19][C:20]1[CH:21]=[C:22]([C@H:28]2[NH:33][C@@H:32]([CH2:34][OH:35])[CH2:31][O:30][CH2:29]2)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>ClCCl>[OH:35][CH2:34][C@H:32]1[CH2:31][O:30][CH2:29][C@@H:28]([C:22]2[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=2)[N:33]1[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: OC[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1cc(F)c(F)c(F)c1
Yield: 99 %

Procedure:
9-Fluorenylmethyl chloroformate (327 mg) was added to a mixed solution of [(3S,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]methanol (250 mg) in dichloromethane (5 mL) and a saturated sodium bicarbonate solution (5 mL), and the reaction solution was stirred at room temperature for six hours. Dichloromethane and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane->heptane:ethyl acetate=2:1) to obtain 470 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=O)[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:11][CH2:12][N:13]1[C:32](=[O:31])[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: CCn1nc(C2CCC2)c2cc(N3CCN(C(=O)Cc4nnc[nH]4)[C@@H](Cc4ccccc4)C3)ccc21
Yield: 10 %

Procedure:
Prepared using the same procedure described in Example 275 from 5-((S)-3-benzyl-piperazin-1-yl)-3-cyclobutyl-1-ethyl-1H-indazole and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 7 days to afford the title compound as a colorless solid (19 mg, 10%). LC/MS (Method B) 3.39 min, [M+1]+ 484.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:36]=[CH:35][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2]>C1COCC1.CO.O.[OH-].[Li+]>[C:1]([C:3]([C:6]1[CH:36]=[CH:35][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[S:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc2)s1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-(5-(4-(4-(2-cyanopropan-2-yl)benzamido)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (Example 85, 65 mg) in THF (1 ml), methanol (1 ml) and 1M lithium hydroxide monohydrate (0.51 ml) was added and reaction mixture was stirred overnight at RT. Organic solvent was concentrated and added water, dilute HCl was added under stirring to pH acidic. The reaction mixture was filtered, to obtain the title compound. Yield: 22 mg (35%). 1HNMR (DMSO-d6, 300 MHz): δ 13.0 (bs, 1H), 10.49 (s, 1H), 8.4 (s, 1H), 8.37 (d, 1H), 8.04 (d, 2H), 7.93 (d, 2H), 7.81 (d, 2H), 7.71 (d, 2H), 4.31 (m, 1H), 2.25 (m, 1H), 1.74 (s, 6H), 0.97 (m, 6H); MS (ES+) m/z 491.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([NH:22][CH:23]=[NH:24])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:21])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:8]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>O1CCOCC1>[CH3:3][C:4]1[N:5]2[C:6]([C:25](=[O:26])[NH:24][CH:23]=[N:22]2)=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:21])[C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:8]=1
Reactant: Cc1ccc(-c2c(-c3cn(NC=N)c(C)n3)cnn2C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(-c3nc(C)n4nc[nH]c(=O)c34)cnn2C)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.60 mmol) was added to a solution of N-{2-methyl-4-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H-imidazol-1-yl}imidoformamide (70 mg, 0.24 mmol) in 1,4-dioxane (4.0 mL), and the mixture was heated at 75° C. for 10 minutes. The reaction was cooled, treated with 1,1′-carbonyldiimidazole (135 mg, 0.833 mmol), allowed to stir at room temperature for 30 minutes, and then heated to 100° C. for 18 hours. After the reaction cooled to room temperature, it was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 10% methanol in ethyl acetate) afforded the product as a white solid. Yield: 55 mg, 0.17 mmol, 71%. LCMS m/z 321.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 2.34 (br s, 3H), 2.36 (s, 3H), 3.71 (s, 3H), 7.22 (br d, J=8 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.79 (s, 1H), 7.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:14][N:15]=2)[NH:10][N:9]=1.C(Cl)(Cl)(Cl)[Cl:27]>>[Cl:27][C:14]1[N:15]=[C:16]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][NH:10][C:11]2=[N:12][C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: Fc1ccc(Oc2cnc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Reactant: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Oc2nc3[nH]nc(-c4ccccc4Cl)c3nc2Cl)c(F)c1

Procedure:
A suspension of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-b]pyrazine (2.70 g, 7.5 mmol) in 500 mL carbon tetrachloride was bubbled with chlorine gas for 16 hours at room temperature while stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (methylene chloride/hexanes 2:3 to 1:0) to give 1.21 g of 5-Chloro-3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyrazine. Mass spec. M+1=394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:15]\[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)/[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.NCC(O)=O.[CH2:31]1N2CN3CN(C2)[CH2:33][N:32]1C3.Cl>CN1CCCC1=O.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:15]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)[CH2:33][NH:32][CH2:31]3)[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Agent: Cl
Agent: NCC(=O)O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Temperature: 140 °C
Reaction time: 0.21 h
Yield: 179.4 %

Procedure:
A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.00 kg, 2.69 mol), glycine (0.50 kg, 6.72 mol) and hexamethylenetetramine (0.28 kg, 2.02 mol) in 1-methyl-2-pyrrolidinone (5.00 L) and toluene (2.50 L) was heated at 140° C. for 7-8 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, the mixture was cooled to 40-50° C. and filtered. The filtered solid was washed with toluene (0.67 L). To the filtrate was added HCl (1M, 13.33 L, 13.33 mol). The resulting biphasic mixture was heated to 50-60° C. and was stirred for 10-15 minutes. The aqueous phase was separated and the organic phase was washed with HCl (1M, 1.67 L, 1.67 mol) at 60-80° C. The aqueous phases were combined and were stirred at 80° C. for 2 hours. The solution was cooled slowly in 3-4 hours to 20-25° C. with gentle stirring and seeding. Crystallization occurred and the resulting suspension was put aside at 20-25° C. for at least 16 hours with occasional stirring, cooled to 0-5° C. in 2 hours, stirred gently at 0-5° C. for 2 hours and then filtered. The filter cake was washed with ice water (2×2.50 L) and dried at maximum 40° C. to a constant weight. 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt (1.09 kg, 90%) was obtained as beige crystalline solid. mp=183-185° C. 1H NMR (DMSO-d6): 7.87(2H, d, J=8.1 Hz), 7.61 (1H, m), 7.40 (2H, d, J=8.1 Hz), 6.68 (2H, m), 4.17 (1H, m), 3.85 (2H, m), 3.76 (2H, m), 3.43 (3H, s), 3.24(2H, s). 13C NMR (DMSO-d6): 14 Carbons (170.84, 152.92, 137.35, 133.94, 132.87, 132.35, 128.01, 124.50, 118.12, 111.30, 71.42, 46.57, 45.11, 25.51). Anal. Calcd for C20H17Cl3N4O2+1.3 H2O: C, 50.51; H, 3.91; N, 11.79; Cl, 22.39. Found: C, 50.56; H, 3.86; N, 11.58; Cl, 21.98; KF, 5.12.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30]>CN(C=O)C.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]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27]([C:36]4[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Temperature: 90 °C

Procedure:
4.3 ml of 2 M aqueous sodium carbonate solution and 116.9 mg (0.14 mmol) of PdCl2(dppf) are added to a mixture of 1104 mg (2.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 475 mg (2.86 mmol) of 3-carboxyphenylboronic acid in 10 ml of DMF. The reaction mixture is heated at 90° C. for 18 h and then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, concentrating and drying under high vacuum result in 724 mg (59.2% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:38]1([OH:42])[CH2:41][CH2:40][CH2:39]1>[Cu]I>[CH:38]1([O:42][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: OC1CCC1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Nc1cc2ccc(OC3CCC3)cc2cn1)C1CC1
Temperature: 130 °C
Reaction time: 12 h
Yield: 12 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.51 mmol), copper(I) iodide (96 mg, 0.51 mmol), 1,10-phenanthroline (100 mg, 0.51 mmol) and cesium carbonate (216 mg, 0.62 mmol) were combined in stainless container, and cyclobutanol (3.0 mL) was added. The reaction mixture was stirred at 120-140° C. for 12 h under nitrogen. It was concentrated and purified by HPLC and TLC to give the product (17.1 mg, 12.0%). LCMS (ESI): RT (min)=1.15, M+H+=282.9, method=A. 1H NMR (400 MHz, DMSO-d6) 10.75 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.26 (d, J=6.8 Hz, 2H), 4.77 (t, J=6.8 Hz, 1H), 2.07-1.65 (m, 6H), 1.19 (s, 1H), 0.79-0.76 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=1>>[CH3:37][C:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[O:12][C:11]3=[O:28])[CH3:9])=[CH:4][CH:3]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method 2 tR=1.001, m/z=477.1; 1H NMR (CDCl3) 1.05-1.23 (d, 6H), 1.49 (d, 3H), 2.10-2.23 (m, 4H), 2.31-2.42 (m, 1H), 2.56 (s, 6H), 2.89 (m, 1H), 5.67 (m, 1H), 6.92-7.07 (m, 4H), 7.08 (s, 2H), 7.22 (m, 2H), 7.33 (d, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1
Reactant: OC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (3.06 mL, 35.1 mmol, 2 eq) in methylene chloride (100 mL) under nitrogen was added distilled dimethylsulfoxide (5.00 mL, 70.2 mmol, 4 eq). After 10 min 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidin-4-ol (described in example 1l) (5.96 g, 17.5 mmol) was added as a methylene chloride solution (10 mL). The reaction was stirred at -78° C. for 30 min prior to the addition of triethylamine (19.6 mL, 140 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 1.5 h. The reaction was poured into 2.5N NaOH (100 mL) and the aqueous phase extracted with methylene chloride (3×100 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The crude reaction mixture was purified by flash chromatography over silica gel (400 mL, eluent: 20% ethyl acetate in hexane) to yield 5.53 g (93%) of the title compound. TLC analysis (Rf 0.21, 20% ethyl acetate in hexane). 1H NMR (CDCl3, 250 MHz) 7.26 (m, 1H), 7.13 (m, 3H), 6.95 (m, 3H), 4.28 (s, 1H), 3.49 (s, 2H), 2.94 (t, J=6.1Hz, 4H), 2.62 (s, 2H), 2.43 (t, J=6.0 Hz, 4H) MS (CI, CH4) m/z 338 (M+1,100), 340 (35), 366 (M+29,31)
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29]OC1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=[O:45])=CC=1.C1C=C[NH+]=CC=1>>[Si:1]([O:18][CH:19]([OH:45])[CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)[Si](OCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: c1cc[nH+]cc1
Product: CCCCCC#CCCCC(O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 72 %

Procedure:
Following the procedure reported to prepare analog 25, 1-(tert-butyldiphenylsilyloxy)-11-(tetrahydro-2H-pyran-2-yloxy)undec-6-yne was cleaved with a catalytic amount of PPTS to give the title compound (72%) as a colorless liquid. TLC: EtOAc/hexanes (3:7), Rf˜0.43; 1H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.62 (t, J=5.6 Hz, 4H), 2.06-2.22 (m, 4H), 1.64-1.50 (m, 10H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.82, 134.33, 129.77, 127.84, 80.77, 80.11, 64.06, 62.69, 32.35, 32.10, 29.10, 27.12, 25.60, 25.33, 18.97, 18.78. HRMS calcd for C27H39O2Si [M+1]+ 423.2719. found 423.2718.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:6]=1.Cl.[NH2:27][OH:28].C[O-].[Na+]>CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:23]1[C:24]2[N:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([NH:27][OH:28])=[O:2])=[CH:6][CH:7]=3)[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: NO
Reactant: COC(=O)Cc1ccc(Cn2c3ccccc3c3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cn2c3ccccc3c3ccccc32)cc1)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.8 %

Procedure:
(4-Carbazol-9-ylmethylphenyl)acetic acid methyl ester (25) (0.25 g, 0.8 mmol) and hydroxylamine hydrochloride (0.32 g, 4.6 mmol) were placed under argon and dissolved in 5 mL of methanol. To it was added a 25% sodium methoxide solution in methanol (1.33 g, 6.2 mmol) which resulted in the formation of a white precipitate. The reaction was stirred for 24 h at room temperature after which the reaction was diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude extract was purified by HPLC to yield the title compound (100 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.57 (s, 1H), 8.73 (s, 1H), 8.17 (d, 2H, J=7.7 Hz), 7.61 (d, 2H, J=8.2 Hz), 7.42 (t, 2H, J=7.5 Hz), 7.20 (t, 2H, J=7.4 Hz), 7.11 (m, 4H), 5.62 (s, 2H), 3.18 (s, 2H). 13C NMR (100 MHz, CD3OD): δ 168.9, 140.2, 136.1, 133.8, 128.5, 126.0, 125.0, 122.5, 119.3, 118.4, 108.3, 45.0, 38.4. ESI-HRMS (m/z): [M+H]+ calcd. for C21H18N2O2, 331.1441. found, 331.1445. Analytical HPLC: Purity=99%, tR=6.82 min, Method A.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][CH2:32][CH2:33][N:23]1[C:14]([C:12]1[O:13][C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)=[O:16])=[O:26])[CH3:29]
Reactant: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Reactant: CCOC(=O)C1CCCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Yield: 59.4 %

Procedure:
A solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.098 g, 0.33 mmol), ethyl pipecolinate (Aldrich; 0.139 g, 0.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl) hydrochloride (Avocado; 0.13 g, 0.68 mmol), and N,N-dimethylaminopyridine (0.083 g, 0.68 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester as a colorless oil (0.085 g, 59%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:7]=1)#[N:5]>CO>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]([C:4](=[NH:5])[O:2][CH3:1])=[N:7]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30.37 g (562 mmol) of sodium methoxide are dissolved in 1.5 l of methanol, and 36.45 g (144.5 mmol) of 3-cyano-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (from Example 4A) are added. The mixture is stirred at room temperature for 2 hours and the resulting solution is employed directly for the next stage.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][N:9]([C:38](=[O:39])[CH2:37][N:21]3[CH2:22][CH2:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20]3=[O:19])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCCNC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 24A (0.48 g, 2.00 mmol) in dichloromethane was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.59 g, 2.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.77 g, 4.00 mmol) and N,N-dimethylpyridin-4-amine (0.024 g, 0.20 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.13-7.37 (m, 20H), 4.16 (s, 2H), 4.11 (s, 2H), 3.33-3.40 (m, 2H), 3.24 (t, J=6.4 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 2.39-2.46 (m, 2H), 1.29-1.37 (m, 2H); MS (DCI+) m/z 515 (M+H)+.