Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:21])[CH:10]=[C:11]([O:19][CH3:20])[C:12]2=[O:18].[N-:22]=[N+]=[N-].[Na+]>CO>[CH3:6][C:7]1[C:8]2[C:9](=[O:21])[CH:10]=[C:11]([O:19][CH3:20])[C:12](=[O:18])[NH:22][C:13]=2[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: COC1=CC(=O)c2c(C)cc(C)cc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c(C)cc(C)cc2[nH]c1=O
Yield: 93.4 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (14 mL, Baker), there was added 5,7-dimethyl-2-methoxynaphthalene-1,4-dione (1.00 g, 4.63 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (601 mg, 9.24 mmol, Aldrich) was added in portions over one min. The ice bath was removed and the reaction was allowed to stir at rt for 18 h under N2. Nitrogen evolution was noted. The reaction was added to crushed ice (100 mL) to give a brown suspension. A solution of 30% MeOH/70% CHCl3 (90 mL) was added and vigorously stirred until all the solid had dissolved. The layers were separated and the aqueous portion was extracted with 30% MeOH/70% CHCl3 (2×30 mL). The combined red organic portion was washed with water (1×30 mL), saturated NaHCO3 (1×30 mL) and brine (1×30 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (~1 g). Crystallization from 95% EtOH (dissolved in 40 mL, hot filtered, concd to 25 mL, allowed to cool to rt then in an ice bath) a gave colorless fluffy needles (678 mg, 63%, pure by 1H NMR); mp 237°-238° C.; 1H NMR (DMSO-d6) δ2.25 (s, 3H), 2.29 (s, 3H), 3.70 (s, 3H), 6.28 (s, 1H), 6.90 (s, 1H), 6.94 (s, 1H), 10.94 (s, 1H); 13 C NMR (DMSO-d6) δ 20.66, 56.04, 113.58, 118.69, 127.47, 128.10, 135.44, 137.45, 141.20, 153.83, 160.10, 190.53; IR (KBr) 3207 (m), 3003 (m), 2920 (m), 1682 (s), 1645 (s), 1619 (s), 1241 (m), 1224 (m), 855 (m); MS (m/z) 231 (M+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.[Br:23][CH2:24][CH2:25][CH2:26][C:27]([CH2:39][CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[BrH:23].[CH2:39]([C:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:26][CH2:25][CH2:24][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:40]
Reactant: Cc1ccc(-c2ccccc2C(=O)NC2CCNCC2)cc1
Reactant: CCC(CCCBr)(CC(=O)OC)c1ccccc1
Product: Br
Product: CCC(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C)cc2)CC1)(CC(=O)OC)c1ccccc1

Procedure:
Prepared from 4′-methyl-biphenyl-2-carboxylic acid-piperidin-4-ylamide and methyl 5-bromo-2-ethyl-2-phenyl-pentanecarboxylate.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:52](Cl)[CH2:53]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH2:52][CH3:53])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OCC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 1.30 g 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 22 ml dichloromethane were added 421 mg EDC, 268 mg DMAP and 541 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 550 mg MS (ES+): m/e=738.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C-:15]#[N:16].[K+]>O>[N:1]1([C:8]2([C:15]#[N:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: [C-]#N
Reactant: C1CCNCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Piperidine (44 g, 0.52 mole) was carefully mixed with 45 ml of concentrated HCl and 120 ml of cold water (pH 3-4). To this solution, 50 g (0.52 mole) of cyclohexanone was added, followed by 36 g of KCN in 100 ml of water with vigorous stirring. The resulting solution was allowed to stir at room temperature for overnight. After 2 hours, a white precipitate was formed. The crystalline precipitate was collected by filtration and washed with cold water. Recrystallization from 95% ethanol (300 ml) gave 88 g of white crystalline solid, mp 66°-8° C., in 88% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[N:8][CH2:9][C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([N:8]1[CH2:9][C:10](=[O:12])[O:11][CH:7]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C=NCC(=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Product: COc1ccc(C2OC(=O)CN2C(=O)c2ccccc2)cc1

Procedure:
(R/S)-N-Benzoyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (21) was prepared from sodium N-(para-methoxybenzylidene)-glycinate (2.15 g, 10.0 mM) and benzoyl chloride (1.16 mL, 10.0 mM) following general procedure D and obtained as a white solid after purification by flash column chromatography, using 20% ethyl acetate/petrol as eluant (2.08 g, 70%): mp 130-132° C.; IR (KBr): 1795, 1635 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 6.84-7.55 (m, 10H), 4.35 (br, 2H), 3.78 (s, 3H); 13C NMR (50.3 MHz, CDCl3): 169.4, 169.3, 160.6, 133.6, 131.6, 128.6, 128.3, 127.7, 127.5, 114.3, 89.9, 55.4, 46.7; LRMS (EI): 298 (MH+). Anal. Calcd for C17H15NO4 : C, 68.68; H, 5.05; N, 4.71; found: C, 68.62; H, 5.01; N, 4.57.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].CC1(C)C(C)(C)OB([C:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=2)O1.[C:28]([O-:31])(O)=[O:29].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:5]([O:31][C:28]([N:24]1[CH2:25][CH:26]=[C:21]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[F:12])[CH2:22][CH2:23]1)=[O:29])([CH3:10])([CH3:6])[CH3:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 65 %

Procedure:
Methyl 4-bromo-3-fluorobenzoate (2.261 g, 9.702 mmol) [CAS 849758-12-9] was added to a solution of 1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (3 g, 9.702 mmol) [CAS 375853-82-0] (synthesis described in WO 2004072025 A2 20040826) in 1,4-dioxane (21 ml) and an aqueous saturated solution of NaHCO3 (18 ml). The resulting solution was degassed using a stream of nitrogen and Pd(PPh3)4 (0.561 g, 0.485 mmol) was added to this solution. The reaction was then microwaved in a sealed tube at 150° C. for 5 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was collected, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 6% as eluent). The desired fractions were collected and evaporated in vacuo to yield D22 (2.107 g, 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:24](OC)(OC)(OC)[CH3:25]>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:24]1[CH3:25]
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Reactant: COC(C)(OC)OC
Product: Cc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Yield: 67.3 %

Procedure:
The general method described in Step 3 of Example 6 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (8.0 g, 25.4 mmol) by reaction with trimethyl orthoacetate (3.6 g, 30 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinoline (5.80 g) as a solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]([F:47])([F:46])[C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.ClC1C=CC(N)=NC=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:42]5[S:43][CH:44]=[C:40]([C:39]([F:47])([F:46])[F:38])[N:41]=5)=[CH:27][C:26]=4[NH2:34])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: Nc1ccc(Cl)cn1
Product: Nc1cc(C(=O)Nc2nc(C(F)(F)F)cs2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of the product from Example 19C was reacted with 4-Trifluoromethyl-thiazol-2-ylamine using the procedure of Example 19D substituting 4-Trifluoromethyl-thiazol-2-ylamine for 5-chloro-2-aminopyridine followed by reduction of the nitro group following the procedure of Example 19E to provide the title product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (3) (923 mg, 2.99 mmol) and 2-methylpropane-2-sulfinamide (1.450 g, 11.96 mmol, 4 eq.) in anhydrous THF (75 mL) was added Ti(OEt)4 (5.46 g, 4.96 mL, 23.92 mmol, 8.0 eq). The resulting mixture was heated to reflux overnight. LC-MS showed ca. 45% conversion. After another 8 h, no further improvement. To the refluxing mixture was added 2-methylpropane-2-sulfinamide (0.725 g, 5.98 mmol, 2 eq.) and Ti(OEt)4 (2.73 g, 2.5 mL, 11.96 mmol, 4.0 eq) and followed by another equal portions of 2-methylpropane-2-sulfinamide and Ti(OEt)4 after 14 hours. The reaction mixture was refluxed for another 2 days, 93% conversion achieved at this point. The reaction was quenched with brine (3 mL) after cooled down to room temperature. The mixture was stirred for another 30 min before filtered through a short pad of Celite®. The filter cake was washed with EA, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography. The fraction of desired product with 2-methylpropane-2-sulfinamide was dissolved in EA (100 mL) and washed with saturated aqueous NaHCO3 (45 mL), 1 M NaOH (40 mL) and brine successively. Solvent was removed under reduced pressure after dried over Na2SO4 and filtered to afford 0.968 g of the desired product 4 as a light yellow solid. MS ESI+ve m/z 412 (M+H)+.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([NH2:17])[CH:16]=1)[NH:13][C:12]([C:18]1[S:19][CH:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH2:21][N:22]=1)=[CH:11]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35].N1C=CC=C[CH:39]=1>C(OCC)(=O)C.C(OCC)C>[C:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([N:17]([CH3:39])[S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)(=[O:36])=[O:35])[CH:16]=1)[NH:13][C:12]([C:18]1[S:19][CH:20]([CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH2:21][N:22]=1)=[CH:11]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc(N)c3[nH]2)S1
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 7-amino-2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-5-yl pivalate (2.55 g) in pyridine (50 mL) was added dropwise a pyridine solution (10 mL) of pyridine-2-sulfonyl chloride (1.27 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with ethyl acetate and diethyl ether, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (1.1 g) and methyl iodide (0.45 mL) were added under ice-cooling. The mixture was stirred at room temperature for 30 min, diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=95:5-4:6) to give the title compound (3.1 g, yield 87%) as a pale-yellow amorphous powder.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1
Reactant: CCC(CC)c1ccc(C#N)c2nc(Cl)n(C)c12
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C#N)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Temperature: 120 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (250 mg, 0.957 mmol), 2-bromo-4-chlorophenol (595 mg, 2.87 mmol), potassium carbonate (397 mg, 2.87 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 120° C. for 12 h under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 2-30% ethyl acetate/n-hexane gradient mixture and crystallized from methanol to afford the title compound as colorless crystals (134 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)=[CH:27][N:26]=1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)=[CH:27][N:26]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)ccc1C=Cc1nc(COc2ncc(CCCCn3ccnn3)cn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.39 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.046 g, 0.47 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.085 g, 0.36 mmol) is added slowly and stirred for further 3 h at r.t. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine is obtained as a colorless solid. Yield 0.125 g (77%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Into a round-bottom flask, was placed a solution of tert-butyl 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (compound 1.2, 2 g, 6.61 mmol, 1.00 equiv) in pyridine (40 mL). POCl3 (10.16 g, 66.26 mmol, 10.02 equiv) was carefully added. The resulting mixture was stirred under nitrogen overnight at room temperature and then concentrated under vacuum. The residue was taken up in 20 mL of DCM, washed with 2×20 mL of sodium bicarbonate (aq), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with PE/EtOAc (100:1-30:1) as eluent to yield 1.4 g (74%) of the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(C)=O.[O:16]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]12>O1CCCC1.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:20]3[CH2:21][CH:17]([OH:16])[CH:18]=[CH:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: C1=CC2OC2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.4 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.30 g, 1.14 mmol) and dimethyl sulfoxide (3 mL) was stirred at ambient temperature in the dark for 2 minutes and cooled to 0° C. A solution of 2,4a-dihydro-1aH-cyclopenta[b]oxirene (0.14 g, 1.72 mmol) in tetrahydrofuran (3 mL) was added into the mixture at 0° C. and stirred at 0° C. for 3 hours. The mixture was stirred at ambient temperature overnight and purified by preparative HPLC to yield 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.24 g, 0.70 mmol) as a white solid: RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 4.23 min. MS: MH+ 344.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[C:13]([O:15]CC)=[O:14].C(O)(=O)C>[OH-].[Na+].CO.O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)[C@H](CCCCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: NCCCCCCCC[C@H](N[C@H]1COc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 3(S)-[9-amino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.2 g) in 1N sodium hydroxide solution (6 ml) is allowed to stand for 30 minutes at room temperature. Acetic acid (1.5 ml) is added and the resulting mixture is subjected to Amberlite XAD-2 column chromatography using methanol-water (1:2) as an eluent. The eluate is concentrated in vacuo and lyophilized to yield 3(S)-[9-amino-1(S)-carboxynonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.15 g) as colorless powder.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[S:44][CH:45]=[CH:46][N:47]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2nccs2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl(2-thiazolyl)tin were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 434 (M+H).