Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH:19]1[CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C(O)C>[N:19]1([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[N:3]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: C1CNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(N2CCC2)nc2ccccc21
Temperature: 50 °C

Procedure:
2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (0.5 g) was placed in a flask with azetidine (0.48 mL), Hunig's base (iPr2Net, 1.5 mL) in 1 mL of ethanol. The reaction was heated to 50° C. overnight and then concentrated to dryness to get 0.55 g of crude 2-(azetidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)(=O)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:45]2)=CC=1.N1C=CC=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[S:45][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)[CH:16]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nnc(C)s3)[nH]2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
N′-Acetyl-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carbohydrazide (58.1 mg, 0.116 mmol) synthesized in Example (22a) was dissolved in toluene (4 mL), 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (63.5 mg, 0.157 mmol) and pyridine (20 μL, 0.25 mmol) were added, and stirring was carried out at 90° C. for 5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-80%) to afford the desired compound (50.6 mg, yield 87%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][N:60]1[C:64]([NH2:65])=[CH:63][CH:62]=[N:61]1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:65][C:64]3[N:60]([CH3:59])[N:61]=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cn1nccc1N
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol) and HATU (201 mg, 0.527 mmol) in DMF (3 mL) was added Hunig's base (0.15 mL, 0.88 mmol), and the mixture was stirred at room temperature for 15 minutes. 1-Methyl-1H-pyrazol-5-amine (51 mg, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed the reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (180 mg) as a yellow solid. LC-MS (ES) m/z=421 [M+H]+.
Reaction SMILES: Cl.C1(C(C2C=CC=CC=2)[N:9]2[CH2:12][C:11]([CH3:14])([OH:13])[CH2:10]2)C=CC=CC=1.C(N(CC)CC)C.P([O-])([O-])(O)=O.[K+].[K+].[F:35][C:36]1[CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[CH:39]=[CH:40][C:41]=1F>CS(C)=O.[OH-].[OH-].[Pd+2].O.ClCCl.CCCCCC.C(OCC)(=O)C.CO.O1CCCC1>[F:35][C:36]1[CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[CH:39]=[CH:40][C:41]=1[N:9]1[CH2:12][C:11]([OH:13])([CH3:14])[CH2:10]1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Pd+2]
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC1(O)CN(c2ccc([N+](=O)[O-])cc2F)C1
Yield: 96 %

Procedure:
A solution of 1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride (3.00 g, 10.4 mmol) in 2:1 methanol/tetrahydrofuran (60 mL) was treated with triethylamine (1.00 g, 1.40 mL, 10.4 mmol) and then palladium hydroxide/carbon (0.300 g) under a N2 stream. The mixture was shaken on a Parr apparatus under 40 psi H2. TLC analysis (2:1 hexane/ethyl acetate) after 2.5 h revealed the hydrogenolysis to be complete. The reaction mixture was filtered through Celite® (dichloromethane wash) and the filtrate concentrated under reduced pressure to give an oil which was immediately taken-up in dry dimethyl sulfoxide (15 mL) and treated with dipotassium hydrogen phosphate (3.40 g, 19.8 mmol) and 3,4-difluoronitrobenzene (1.60 g, 1.10 mL, 9.9 mmol) at ambient temperature under N2. After stirring 16 hours at his temperature, TLC analysis (2:1 hexane/ethyl acetate) revealed the reaction to be essentially complete. The reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL) and water (150 mL). After shaking, the organic phase was separated. The aqueous phase was back-extracted with dichloromethane and the combined organic extracts washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to an oil. Chromatography over silica gel, eluting with 3:1 hexane/ethyl acetate, afforded, after concentration of appropriate fractions, 2.15 g (98%) of the title compound as an orange solid with mp 109°-110° C. and MS(EI) 226 (M+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[CH:22]=[C:21]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH:20]=[CH:19][N:18]=1)=[O:16])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH-].[K+]>C1COCC1.O>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C(=O)c2cc(CO)ccn2)[nH]c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a solution of 3-acetylamino-6-chloro-2-[4-[(tert-butyldimethylsilyloxy)methyl]pyridine-2-carbonyl]indole (step 6, 240 mg, 0.454 mmol) in THF (10 ml) was added 1M TBAF in THF (0.7 ml, 0.681 mmol) at 0° C. After stirring for 30 min, potassium hydroxide (90 mg, 1.36 mmol) in water (2 ml) was added at 0° C. The mixture was stirred for an additional 1 h at room temperature and concentrated. The residue was diluted with ethyl acetate (100 ml), and then washed with water (30 ml×2) and dried (MgSO4). Removal of solvent gave a crystalline residue, which was recrystallized from dichloromethane to afford 52 mg (33%) of the title compound. m.p.: 216-218° C. (recrystallized from dichloromethane)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:56]1[C:57]([O:65][CH3:66])=[N:58][CH:59]=[C:60]([N+:62]([O-:64])=[O:63])[CH:61]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:66][O:65][C:57]1[C:56]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:61][C:60]([N+:62]([O-:64])=[O:63])=[CH:59][N:58]=1
Reactant: COc1ncc([N+](=O)[O-])cc1Br
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc([N+](=O)[O-])cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Morpholine (54 μl), cesium carbonate (336 mg), Pd2(dba)3 (57 mg), and Xantphos (72 mg) were added to a 1,4-dioxane (3 ml) solution containing 3-bromo-2-methoxy-5-nitropyridine (96 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 10 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a yellow solid of 2-methoxy-3-morpholino-5-nitropyridine (54 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26](O)=O)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[CH:3][CH:4]=[C:5]5[CH:6]=[CH:7][NH:8][C:9]5=4)[N:1]=3)=[CH:24][C:23]([C:29]([F:32])([F:30])[F:31])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1ccc2cc[nH]c2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cc[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of 79 mg (0.45 mmol) of 6-amino-1H-indole-7-carboxylic acid in 7 mL of acetonitrile, is added 130 mg (0.45 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 0.16 mL (2.06 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 0.12 mL (1.57 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 0° C. during 30 minutes and 2 hours at ambient temperature. After evaporation of the solvent, the residue is triturated with a minimum of cold water. The precipitate which is formed is filtrated and washed with cold water. The residue is then purified by column chromatography on silica gel with hexanes and ethyl acetate as eluents and 47.1 mg (0.11 mmol, 25%) of a yellowish solid are obtained; LC/MS:432/434 (M+H)+.
Reaction SMILES: [CH2:1]1[C:6](=O)N(Br)[C:3](=[O:4])[CH2:2]1.CC1C=C[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH:3]([C:2]1[CH:1]=[CH:6][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=1)=[O:4]
Reactant: Cc1ccc2sccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc2sccc2c1
Reaction time: 0.25 h
Yield: 297.4 %

Procedure:
Under N2, NBS (6 g, 0.034 mol) was added to a solution of 5-methylbenzo[b]thiophene (30.8 g, 0.21 mol), benzoylperoxide (1.6 g) in CCl4 (300 ml) and was heated at reflux. After 15 minutes, the remainder of the NBS (35 g, 0.2 mol) was added over a period of 5 minutes and heated at reflux for 1.5 hours. The reaction mixture was then cooled, filtered and the filtrate washed with H2O (2x), dried, filtered and concentrated to dryness. The residue was dissolved in CHCl3 (130 ml) and added to a solution of hexamethylenetetramine (33.6 g, 0.24 mol) in CHCl3 (60 ml). After 0.5 hour, the reaction mixture was cooled, filtered and the solid washed with hexane. After drying, the solid was dissolved in acetic acid-H2O (275 ml) and heated at reflux for 2 hours. Then concentrated HCl (55 ml) was added and the mixture refluxed an additional 5 minutes. After cooling, the solution was extracted with ether (3×), and the organic extracts were backwashed with saturated Na2CO3 (2×), dried, filtered, and concentrated to dryness to yield 16.4 g (48%) of product
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.O1[C:29]2([CH2:34][CH2:33][CH:32]([C:35](=[S:37])[NH2:36])[CH2:31][CH2:30]2)[O:28]CC1.CC(C)=O.Cl>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:36]=[C:35]([CH:32]2[CH2:33][CH2:34][C:29](=[O:28])[CH2:30][CH2:31]2)[S:37][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: NC(=S)C1CCC2(CC1)OCCO2
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCC(=O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
The 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.622 g, 1.57 mmol, Preparation #A.2) and 1,4-dioxaspiro[4.5]decane-8-carbothioamide (0.317 g, 1.57 mmol) were dissolved in DMF (5 mL) then stirred at ambient temperature for about 12 h. The mixture was concentrated under reduced pressure then acetone (25 mL) and concentrated hydrochloric acid (2 μL, 10 mmol) were added. The mixture was heated to about 60° C. for about 1.5 h then concentrated under reduced pressure, basified with 50% NaOH and diluted with water. The mixture was extracted with ethyl acetate then organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/MeOH (95:5) as an eluent to give the title compound (0.495 g, 69%): LC/MS (Table 1, Method b) Rt=2.14 min; MS m/z: 454.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]([F:32])[C:22]=1O.B(O)(O)O>CN(C=O)C.C(Cl)Cl>[F:32][C:23]1[C:22]2[O:13][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[N:20][C:21]=2[CH:26]=[CH:25][C:24]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccccc34)oc2c1F
Temperature: 0 °C
Yield: 3.7 %

Procedure:
To 1-methylindole-3-carboxylic acid (917 mg, 5.23 mmol) was added methylene chloride (20 ml). Under stirring at 0° C., oxalyl chloride (0.68 ml, 7.85 mmol) and DMF (catalytic amount) were added. After stirring at room temperature for 1.5 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was added with xylene (20 ml). Methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.0 mmol) and boric acid (539 mg, 8.72 mmol) were added to the resulting mixture, followed by stirring at 160° C. for 3 days. After the reaction mixture was cooled to room temperature, ice water was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column to collect chloroform/ethyl acetate (10/1) eluate fractions and then, purified by chromatography using a thin layer plate, whereby from chloroform/acetone (10/1) eluate fractions, methyl 7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolylacetate (62 mg, 4%) was obtained as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [H][H]
Reactant: COc1ccc(C#CCCO)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCO)cc1OC
Yield: 93.2 %

Procedure:
A mixture of 2.0 g of 4-(3,4-dimethoxyphenyl)-3-butyn-1-ol and 0.2 g of 10% palladium on carbon in 40 mL of ethanol was stirred in a hydrogen atmosphere for 4 hours. After filtration, the filtrate was concentrated under reduced pressure to give 1.9 g of 4-(3,4-dimethoxyphenyl)butan-1-ol as an oil.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)OB([C:27]2[CH:31]=[CH:30][N:29]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:28]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:31]=[CH:30][N:29]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.51 mmol) in 1,4-dioxane (5.0 mL) and water (3 drops) was added 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[tris(propan-2-yl)silyl]-1H-pyrrole (356 mg, 1.02 mmol), Pd(PPh3)4 (29.4 mg, 0.03 mmol), and sodium carbonate (108.1 mg, 1.01 mmol) with stirring for 1 hour at 90° C. under an atmosphere of nitrogen. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2-yl)amino]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate as a yellow solid (130 mg, 53%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])(C)(C)C.[Li][CH2:35][CH2:36][CH2:37]C.CN1C(=O)N(C)CCC1.C(Br)C=C>C1COCC1>[F:15][C:12]([F:14])([F:13])[C:7]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:37][CH:36]=[CH2:35])=[CH:20][CH:21]=1)([OH:6])[C:8]([F:10])([F:11])[F:9]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CS(=O)(=O)c2ccccc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: C=CCBr
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C=CCC(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Tert-Butyl(dimethyl)[2,2,2-trifluoro-1-{4-[(phenylsulfonyl)methyl]phenyl}-1-(trifluoromethyl)ethoxy]silane (378 mg, 0.74 mmol) was dissolved in anhydrous THF (10 mL) under argon and cooled to −78° C. 1.6M BuLi solution in hexanes (0.5 mL, 0.85 mmol) was added and the reaction was allowed to warm to 0° C. After 30 min at 0° C., the reaction was cooled to −78° C. and DMPU (0.26 mL, 2.1 mmol) was added, followed by allyl bromide (0.07 mL, 0.81 mmol). The reaction was allowed to warm to 0° C. and monitored by thin layer chromatography. The reaction was quenched with saturated NH4Cl and diluted with ethyl acetate. The layers were separated and the organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (6:1 hexanes/EtOAc) afforded the protected sulfone as a colorless oil. The sulfone was deprotected as described in Example 2 step 3. Purification by flash chromatography (6:1 hexanes/EtOAc) afforded the title compound as a white solid (266 mg, 82%): mp=148° C. 1H NMR (CDCl3) δ 7.55 (m, 3H), 7.45 (d, 2H), 7.33 (t, 2H), 7.17 (d, 2H), 5.55 (m, 1H), 5.04 (m, 2H), 4.14 (dd, 1H), 3.51 (br s, 1H), 3.21 (m, 1H), 2.93 (m, 1H). Anal. Calc. for C19H16O3SF6: C, 52.06; H, 3.68. Found: 52.04; H, 3.45. HRMS (M+NH4+) Calc.: 456.1068. Found: 456.1075.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]=O)=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CCO.CC(O)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(CN2CCOCC2)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (30 mg), morpholine (36 μl) and AcOH (0.1 ml) in EtOH (1 ml) was added sodium cyanoborohydride (15 mg) at room temperature and stirred at room temperature for 5 hours. The reaction mixture was acidified to pH 3 with HCl and stirred for 30 minutes. The solution was neutralized with aqueous NaOH and extracted with EtOAc (×3). The organic layer was combined, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel(CHCl3-MeOH 97:3) to give ethyl 3-[1-ethyl-4-(5-methyl-3-pyridyl)-6-(4-morpholinylmethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (35 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 32 g of N-benzyloxycarbonyloxysuccinimide in 100 ml of tetrahydrofuran is reacted with 15 g of 6-amino-1-hexanol in 30 ml of 50% methanol:tetrahydrofuran. The reaction mixture is stirred overnight at room temperature, and poured into water. The resulting mixture is extracted with methylene chloride and the organic layer is washed with sodium chloride solution, dried over anhydrous magnesium sulfate. The magnesium sulfate is filtered and the solvent is removed by evaporation. The product is recrystallized from ethyl acetate/ether to provide N-(benzyloxycarbonyl)-6-amino-1-hexanol, mp 81.5°-83° C. having the following formula: ##STR31##