Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH:17]3[CH2:22][CH2:21][CH:20]([C:23]([NH2:25])=O)[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[OH-].[Na+]>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][NH2:25])[CH2:21][CH2:22]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: NC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 6 h
Yield: 51.7 %

Procedure:
Lithium aluminum hydride (58 mg, 1.54 mmol) was added to a solution of the 4-(1H-indazol-5-yloxy)cyclohexanecarboxamide (100 mg, 0.386 mmol) obtained in Example 369 in tetrahydrofuran (3 ml), and the resulting mixture was refluxed. After 6 hours, water (0.087 ml), a 2M-aqueous sodium hydroxide solution (0.176 ml) and then water (0.261 ml) were added to the reaction mixture, and the resulting solution was filtered by the use of Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain 1-[4-(1H-indazol-5-yloxy)cyclohexyl]methanamine (49 mg, 52%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O.O1CCCC1>[C:1]1([C:7]2[N:8]=[N:9][N:10]([C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a suspension of 5.0 g (34.2 mmol) of 5-phenyltetrazole in 55 mL of acetone was added 5.0 mL of triethylamine (3.6g, 35.6 mmol, 1.04eq). After 15 minutes, a solution of 10.0 g of triphenylmethyl chloride (35.9 mmol, 1.05eq) in 20 mL of tetrahydrofuran was added and the mixture stirred at room temperature for one hour. Water (75 mi) was slowly added and the mixture stirred for one hour at room temperature. The product was collected by filtration, washed with 75 mL of water and dried at 60° C. under vacuum to give 13.3g (34.2 mmol, 100%) of the product.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]1[C:14](=[O:15])[C@H:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][C@H:11]1[C:19](OCC1C=CC=CC=1)=[O:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>O1CCCC1.C(OCC)(=O)C.C(O)C>[C:3]([O:7][C:8]([N:10]1[C@H:11]([CH2:19][OH:20])[CH2:12][C@@H:13]([CH:16]([CH3:17])[CH3:18])[C:14]1=[O:15])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1=O
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A suspension of 27 g of lithium borohydride in 15 mL of anhydrous tetrahydrofuran is cooled to 10° C. and a solution of 15.4 g of (2S,4S)-4-isopropyl-5-oxo-pyrrolidine-1,2-dicarboxylic acid-2-benzyl ester-1-tert-butyl ester in 80 mL of tetrahydrofuran is added within 2 hours. The resulting suspension is warmed to 40° C. and stirred for a further 3 hours. Water (800 mL) is then added and the mixture filtered. The solid is then suspended in 700 mL of tetrahydrofuran and heated to reflux for 75 minutes. After this time the mixture is cooled to 25° C. and filtered. The filtrate is treated slowly with 500 mL of a 1.0 M solution of oxalic acid in water at room temperature. The resulting suspension is filtered and the solid washed with 500 mL of tetrahydrofuran. The solvent is then removed from the filtrate to provide an oil. The oil is re-dissolved in a mixture of 630 mL of ethyl acetate and 0.07 L of ethanol at elevated temperature and the slightly cloudy solution filtered. The clear solution is cooled to −25° C. and the resulting suspension stirred for 2 hours. The solid is collected by filtration, washed with ethyl acetate and dried to give (3S,5S)-5-hydroxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:20])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=1.[H-].[Na+].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[Cl-].[NH4+]>O1CCCC1.O.N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH:20][S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][N:17]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CSc1cnc(OCCOc2ncnc(N)c2Br)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Br)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
To a solution of 5-bromo-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]pyrimidine-4-amine (102 mg) in tetrahydrofuran (2 ml) is added sodium hydride (60% dispersion-type, 34 mg), and thereto is added 4-tert-butylbenzenesulfonyl chloride (198 mg). The mixture is stirred at room temperature for 20 minutes, and thereto are added a drop of pyridine and water. The mixture is stirred at room temperature for 30 minutes, and neutralized with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by preparative thin layer chromatography (solvent; chloroform/methanol=15:1), and recrystallized from hexane/ethyl acetate to give N-{5-bromo-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (135 mg). The physical properties thereof are the same as those of the compound obtained in Reference Example 16-(4).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:24]3[C:25]4[N:16]([CH2:17][CH2:18][O:19][C:20]=4[CH:21]=[C:22]([O:26][CH2:27][CH2:28]O)[CH:23]=3)[N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CS(OS(C)(=O)=O)(=O)=O.[CH2:39]([N:41](CC)CC)C.CN.[ClH:48].CCOCC>C(Cl)Cl.CS(C)=O.O>[ClH:48].[CH3:39][NH:41][CH2:28][CH2:27][O:26][C:22]1[CH:23]=[C:24]2[C:25]3=[C:20]([O:19][CH2:18][CH2:17][N:16]3[N:15]=[C:14]2[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])[CH:21]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn2c3c(cc(OCCO)cc13)OCC2
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CNCCOc1cc2c3c(c1)c(S(=O)(=O)c1cccc4ccccc14)nn3CCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[2-(naphthalene-1-sulfonyl)-7,8-dihydro-6-oxa-1,8a-diaza-acenaphthylen-4-yloxy]ethanol (0.41 g, 1.0 mmoles), methane sulfonic anhydride (Ms2O) (0.176 g, 1.05 mmoles) and triethylamine (0.143 ml, 1.05 mmole) in CH2Cl2 was stirred at 0° C. to room temperature for 5 hours and concentrated in vacuo to give a residue. A mixture of the residue and methylamine (0.5 ml of 1M solution in THF, 0.5 mmoles) in DMSO was stirred overnight at 70° C., cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, treated with 1M HCl in ether (0.2 ml, 0.2 mmoles) and evaporated to dryness to afford the title product as a dark pale solid, identified by HNMR and mass spectral analyses, MS: (ES) m/z 423.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].C(Cl)(Cl)Cl.O>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCO
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCC(=O)OCCCCCCCCCCCC(=O)O
Reaction time: 4 h
Yield: 96.7 %

Procedure:
12-Hydroxydodecanoic acid (1 g) was dissolved in pyridine, and butyroyl chloride (0.59 g) was added to the solution in an ice bath. After 4 hours of stirring, the reaction mixture was distributed into chloroform and water , and the chloroform layer was concentrated to give 12-butyryloxydodecanoic acid (1.28 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]2[N:18]=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH:19]3[CH2:21][CH2:20]3)=[CH:11][C:10]=2[F:26])[CH2:4]1.S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[NH2:2][CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]2[N:18]=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([O:24][CH2:32][CH3:33])=[O:23])=[CH:15][N:16]3[CH:19]3[CH2:21][CH2:20]3)=[CH:11][C:10]=2[F:26])[CH2:4]1
Reactant: CC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1N
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CC(C)C(N)C3)c(F)cc2c1=O

Procedure:
7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (6.6 g) was suspended in absolute ethanol. Sulfuric acid (7 g) was added to the suspension and the mixture was refluxed for 1 hour with stirring. After evaporation of ethanol (ca. 20 ml), absolute ethanol (20 ml) was added and the mixture was again refluxed. This operation was repeated three times and then the mixture was refluxed for 15 hours with stirring. After evaporation of ethanol, chloroform and 20% aqueous sodium hydroxide solution was added to the residue, and the mixture was adjusted to pH>9. The organic layer was separated, chloroform was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give ethyl 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylate (4.3 g), m.p. 148°-150.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[Cl-:9].[Al+3].[Cl-:11].[Cl-].ClCl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:9][C:4]1[CH:3]=[C:2]([C:6](=[O:8])[CH3:7])[S:1][C:5]=1[Cl:11]
Reactant: [Cl-]
Reactant: CC(=O)c1cccs1
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(Cl)s1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 108.9 %

Procedure:
To a solution of 1-Thiophen-2-yl-ethanone (5.0 grams, 40.0 mmole) in chloroform (50 ml) at 20° C. was added portionwise aluminum chloride (15.9 grams, 119.0 mmole). The mixture was stirred at 20° C. for 10 minutes and 1 M Cl2 in carbon tetrachloride (120 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes and diluted with methylene chloride (300 ml) and washed with 1 N sodium hydroxide and water and dried over magnesium sulfate and concentrated to give a solid (8.5 g). MW 195.07; MS (m/e) 196 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1.O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=3[CH:3]=[CH:2]2)=[O:22])[CH:15]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Cc1cccc(N=C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)n2ccc3c(C=O)cccc32)c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Indole-4-carbaldehyde (435 mg) was dissolved in 8 ml of dimethylformamide at room temperature under an argon gas atmosphere, then 126 mg of sodium hydride (content 60%) was added to the resulting solution and the mixture was stirred for 30 minutes, then 439 mg of m-tolylisocyanate was added thereto and the resulting mixture was stirred for one hour. The reaction solution was added to 50 ml of water followed by extraction with ethyl acetate (50 ml×2). The resulting organic phase was washed with water (50 ml×2), dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to give a crude product. This was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1) to give 736 mg of 1-(m-tolylcarbamoyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 88%.
Reaction SMILES: C[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[Cl:14]C1C=CC=C(N)C=1C(OC)=O.N([O-])=O.[Na+].S(=O)=O.S(Cl)(Cl)(=O)=O.[OH-].[NH4+]>C(O)(=O)C.Cl.O>[Cl:14][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7]
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: COC(=O)c1c(N)cccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: O=S=O
Solvent: CC(=O)O
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21
Yield: 62 %

Procedure:
4-Chlorosaccharin was prepared by the same method as used for preparing 4-methylsaccharin using methyl 6-chloro-anthranilate (4.22 g; 22.7 mmol) in acetic acid (22 ml) and conc. HCl (40 ml) and sodium nitrite (1.68 g; 24.3 mmol) in water (7 ml) to prepare the diazonium salt which was added to cupric chloride dihydrate (1.93 g; 11.4 mmol; 0.5 equiv.) and sulfur dioxide (6.5 g; excess) in acetic acid (30 ml)/water (5 ml). The resulting sulfonyl chloride was treated with ammonium hydroxide (150 ml) as previously described to afford 3.07 g (62%) of 4-chlorosaccharin as a pale yellow solid, mp 245°-246° C. 1H nmr (300 MHz, CD3CN): 7.918 (1H, dd, J=7.39, 1.91 Hz); 7.865 (1H, t, J-7.52 Hz); 7.829 (1H, br d, J=7.30 Hz). IR (KBr, CM1): 3570 (s); 3520 (s); 2950 (s,b); 1735 (s); 1630 (m). FDMS: m/e 217 (M+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[CH2:6][C:7]#[N:8].O1CCCC1.[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:19]([CH:6]([C:7]#[N:8])[C:5]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:4]=1[Cl:3])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCc1ccccc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(CCc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.13 mole as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature a solution of 2,4-dichlorobenzyl cyanide (25 g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed, the temperature is maintained at 30° C. for an additional 0.5 hours. A solution of phenethylbromide (26 g., 0.14 mole) is then added dropwise and the resultant reaction mixture is stirred at 40° C. overnight under nitrogen. The reaction mixture is poured into 1 liter of water and extracted with (3×200 ml.) of ether. The combined ether extracts are washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated and the crude product distilled (144°-56°/0.03 mm) to give 26.6 g. (70.5%) of product, which is identified by nmr.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[OH2:13]>C(#N)C>[OH:13][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: N#Cc1ccc(C(=O)CO)cc1

Procedure:
A solution of 1 g of 4-(2-bromoacetyl)benzonitrile in acetonitrile (5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min). The same experiment is conducted five times. All the vials are collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([C:51]3[C:42](=[CH:43][C:44]4[O:49][CH2:48][CH2:47][O:46][C:45]=4[CH:50]=3)[O:41][CH2:40]2)[C:32]1=[O:52]>>[CH3:19][C:15]1([CH3:18])[O:14][C@@H:13]([CH2:12][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]3([C:51]4[C:42](=[CH:43][C:44]5[O:49][CH2:48][CH2:47][O:46][C:45]=5[CH:50]=4)[O:41][CH2:40]3)[C:32]2=[O:52])[CH2:17][O:16]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC1(C)OC[C@H](CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)O1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-t][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (98%): mp 55-57° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30-6.99 (m, 4H), 6.47-6.20 (m, 2H), 4.88-4.84 (m, 1H), 4.63-4.59 (m, 1H), 4.48-4.40 (m, 1H), 4.17-3.77 (m, 8H), 1.35-1.28 (m, 6H); MS (ES+) m/z 410.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OCC)cc1OC
Yield: 68.9 %

Procedure:
A mixture of 50 g of 3-methoxy-4-hydroxybenzeneacetic acid ethyl ester, 66.1 g of powdered potassium carbonate, 70.57 g of 1-bromotetradecane and 500 ml of acetone is heated at reflux temperature for 76 hours. The reaction is cooled, filtered and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2% sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-10% ethyl acetate/hexane) to give 66.6 g of the desired product as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:3]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)=[O:13])[CH:3]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ccc2cc(-c3cc(NC(=O)c4ccccn4)c4cn[nH]c4c3)ccc21
Temperature: 150 °C
Yield: 13.2 %

Procedure:
A mixture of N-(6-bromo-1H-indazol-4-yl)-2-pyridinecarboxamide (100 mg, 0.31 mmol), (1-methyl-1H-indol-5-yl)boronic acid (65 mg, 0.37 mmol, available from Apollo), Pd(dppf)Cl2 (10 mol %, 31 mg, 0.038 mmol), aqueous sodium carbonate solution (2M, 0.468 ml, 0.94 mmol) in dioxane/water 1:1 (3 ml) was heated at 150° C. for 30 mins under microwave irradiation. The reaction mixture was filtered through a silica cartridge eluting with MeOH. The solvent was removed in vacuo. The crude compound obtained was purified by HPLC using the following conditions to provide the title compound (15 mg).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3].ClCCN1CC[CH2:31][CH2:30][CH2:29]1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:21][CH2:31][CH2:30][CH2:29][CH2:20]3)=[CH:14][CH:15]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3]
Reactant: ClCCN1CCCCC1
Reactant: CN(C)CCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1
Product: NC(=O)Nc1cc(-c2ccc(OCCN3CCCCC3)cc2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 10 (a) and N-(2-chloroethyl)piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].CCN(CC)CC.CN1CCCC1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:46]1[CH:47]=[CH:48][C:49]([O:52][CH:53]([F:55])[F:54])=[N:50][CH:51]=1>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:54][CH:53]([F:55])[O:52][C:49]1[N:50]=[CH:51][C:46](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:47][CH:48]=1
Reactant: FC(F)Oc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN1CCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(OC(F)F)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl acrylate (9.99 g, 78.1 mmol, 3.50 equiv.), Et3N (8.5 mL, 60.2 mmol, 2.70 equiv.), N-methyl pyrrolidine (20 mL), Tritolylphosphine (1.17 g, 3.52 mmol, 0.16 equiv.) followed by Pd(OAc)2 (0.50 g, 2.22 mmol, 0.09 equiv.) were added. The temperature was gradually raised to 90° C. and compound 2 (5.00 g, 22.3 mmol, 1.0 equiv.) in NMP (10 mL) was added drop wise and stirred at 90° C. for 12 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through pad of celite and washed with EtOAc (50 mL). The combined filtrate was washed with cold water (2×50 mL) followed by NaOCl (50 mL), brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude residue which was purified by column chromatography (3% EtOAc/hexane) to afford compound 3 (4.0 g, 66%) as yellow solid.