Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Yield: 1 %

Procedure:
A solution containing 67.8% water, 1.2% of potassium carbonate, 25% paraffin, 5% stearic acid and 1% oleic acid is formed by melting the stearic acid, oleic acid and paraffin at about 90° to 100° C. and adding an aqueous solution of the potassium carbonate at 90° to 100° C. The resultant solution is stirred for more than 10 minutes at the temperature of 90° to 100° C. in a mixer at 1500 to 3600 r.p.m. until the apparent volume swells to about twice the original volume. This well stirred solution is cooled to 25° C. under stirring.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]=[N+]=[N-])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>CO.[Pd]>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
The resulting 1-[3,5-bis(trifluoromethyl)phenyl]ethyl azide (crude product: 111.5 mg) was dissolved in methanol (6 mL) and the solution was added with palladium-fibroin (18 mg) for hydrogen substitution, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 5:1) to obtain 77.6 mg of 1-[3,5-bis(trifluoromethyl)phenyl]ethylamine as colorless oil (yield: 91%, for 2 steps).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:19]2=[C:20]3[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]2)[CH:14]=[C:13]([C:22](=[O:24])[CH3:23])[C:12](=[O:25])[C:11]3=[CH:10][C:9]=1[F:26]>CN(C)P(=O)(N(C)C)N(C)C>[N:1]1([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22](=[O:24])[CH3:23])[C:12](=[O:25])[C:11]4=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)CCC2C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)c1cn2c3c(c(N4CCCCC4)c(F)cc3c1=O)CCC2C
Yield: 48.6 %

Procedure:
Anhydrous piperidine (8 g) was added to 5.3 g of 8-chloro-9-fluoro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine. 70 ml of hexamethylphosphoric triamide was added thereto and the mixture was allowed to react at 140° C. on an oil bath for 6 hours. After completion of the reaction any excess solvent and piperidine were removed by distillation under reduced pressure and 100 ml of ethyl acetate was added to the residue to precipitate light yellow crystals. The crystals thus obtained were separated by filtration and 300 ml of water was added thereto followed by adjusting the resulting solution to a pH of 2 with 1N hydrochloric acid. The solution was heated and filtered. The filtrate was concentrated to 50 ml and rendered alkaline with a 10% aqueous sodium hydroxide solution to obtain 3.0 g of 8-(1-piperidyl)-9-fluoro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O.C(N(CC)CC)C.C(OCC)C>[CH2:21]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)[CH:20]=[CH2:19]
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCN1CCN2c3ccccc3Cn3cccc3C2C1
Reaction time: 1 h

Procedure:
To the solution of 4.8 g of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 20 ml of dimethyl formamide and 2.44 g of triethylamine, 2.91 g of allyl bromide are added dropwise while stirring. After one hour, the mixture is diluted with diethyl ether, washed with water and saturated aqueous sodium chloride and the aqueous phase is once more extracted with diethyl ether. The combined organic solutions are washed with saturated aqueous sodium bicarbonate, dried, evaporated and the residue triturated with diethyl ether, to yield the 2-allyl-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine melting at 130°-132°.
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:40])([CH2:20][CH2:21][C:22]1[N:23]([CH3:39])[C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC)=O)(C)(C)C.Br[Si](C)(C)C>ClCCl>[NH2:8][C@:9]([CH3:40])([CH2:20][CH2:21][C:22]1[N:23]([CH3:39])[C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:13])([OH:16])[OH:19]
Reactant: CCOP(=O)(CC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)n1C)NC(=O)OC(C)(C)C)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cn1c(CC[C@@](C)(N)CCP(=O)(O)O)ccc1C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
To a solution of diethyl (3R)-3-t-butoxycarbonylamino-3-methyl-5-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]pentylphosphonate (114.0 mg, 0.20 mmol) obtained in Example (44c) in dichloromethane (2.0 ml) was added bromotrimethylsilane (0.26 ml, 1.97 mmol), and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. After stirring, the reaction mixture was evaporated in vacuo, and the residue was diluted with aqueous ethanol and then adjusted to pH 4 with aqueous ammonia and acetic acid. The crystals precipitated were collected by filtration, washed successively with water and ethanol and dried to afford the title compound (52.0 mg, yield: 63 k).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([I:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccnc(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(I)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 77 %

Procedure:
To a suspension of 2-iodo-isonicotinic acid (can be prepared according to J. Med. Chem. (19) 490, 1976) (24.9 g, 100 mmol) in methanol (100 mL) was added sulfuric acid (concentrated, 11 mL, 205 mmol) and the mixture was stirred at ambient temperature for 5 days followed by heating to reflux for 3 h. The reaction mixture was cooled to ambient temperature, concentrated and poured into ice cold aqueous sodium hydrogencarbonate (half-saturated) and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=85:15 to 80:20) afforded the title compound (20.4 mg, 77%) as a light yellow solid. MS: m/e=263.0 [M]+.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[C:1]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 84.8 %

Procedure:
0.13 g (0.00038 mol) of 1-(4-nitro-benzyl)-piperidin-4-yl benzoate was dissolved in 7.6 ml of ethanol and treated with 0.08 g of Raney-nickel. The mixture was hydrogenated at room temperature and under normal pressure for 2 hrs. The catalyst was filtered off and, after concentration, the residue was chromatographed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.1 g (84%) of 1-(4-amino-benzyl)-piperidin-4-yl benzoate was obtained as a yellowish oil. MS: me/e=311 (C19H23N2 O2+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:25][OH:26].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:26][NH:25][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(CCc3ccccc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15e (125 mg, 0.377 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (262 mg, 3.77 mmol) and a freshly prepared solution of sodium methoxide in methanol (130 mg, 5.655 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of (2-chlorophenyl)acetic acid (15 g, 88 mmol) in conc. H2SO4 (100 mL) was cooled to −20° C. and treated drop-wise with conc. HNO3 (9.4 g, 97 mmol). The resulting mixture was stirred at −20° C. for 0.5 h, poured into the ice-water, and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (2-chloro-5-nitrophenyl)acetic acid (15 g, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.35 (m, 1H), 7.96 (m, 1H), 4.12 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[CH:7]=[CH:6]1.Cl.[CH3:23][NH:24][OH:25]>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:24]([OH:25])[CH3:23])=[O:16])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CNO
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: Cl
Product: CN(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 11.10 (br, 1H), 8.92 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.26-7.38 (m, 2H), 7.07-7.08 (m, 1H), 6.72 (s, 1H), 5.64 (s, 2H), 3.33 (s, 3H). LCMS (API-ES, M+H+): 318.0. HRMS calcd for C16H14F2N3O2(M+H) 318.1054, found 318.1037. HPLC: 100% purity.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=2[N+:31]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(=O)C.[Zn]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=2[NH2:31])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-3-nitropyridin-2-amine (0.361 g, 0.000725 mol) in CH2Cl2 (6.00 mL) and acetic acid (3.00 mL) was added zinc (0.474 g, 0.00725 mol) and the mixture was stirred for 30 min. The suspension was filtered and the filtrate was concentrated. The residue was dissolved in 50 ml EtOAc and 3 ml Et3N then washed with water (2×10 mL). The organic layer was dried (MgSO4) and concentrated to afford the crude product (0.297 g, 88%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[N:14]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:15]=[N:16][C:17]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[N:14]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH:15]=[N:16][C:17]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][N:10]2[S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[CH:6][CH:5]=1
Reactant: Clc1ccc(Cn2cnc(-c3ccccc3)c2-c2c[nH]c3cc(Cl)ccc23)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(-c4ccccc4)ncn3Cc3ccc(Cl)cc3)c3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50% of NaH in mineral oil (284 mg, 5.9 mmol) is added to a solution of Example 1 (1.65 g, 3.9 mmol) in THF (40 mL) at 0° C. The reaction mixture is allowed to warm to rt and stirred for 15 min. TsCl (902 mg, 4.7 mmol) is added and stirring continued for 1 h. The reaction is quenched by addition of EtOAc and H2O. The organic layer is separated, washed with brine, dried and concentrated. The crude product is purified by tituration with EtOAc/hexanes to give the title compound as a white solid. ES-MS: M+H=573.7: EtRet=5.33 min.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[Na+]>CN(C=O)C.C1COCC1>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0° C. solution of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (24 mg, 0.06 mmol) in DMF (1 ml) was treated with Acetic anhydride (0.01 ml, 0.06 mmol). The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc/sat. NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a white solid which was filtered through a Buchner funnel and washed with Et2O and Hexanes to afford a yellow solid. The yellow solid was dissolved in THF (2 ml) and treated with 1N NaOH (0.05 ml, 0.05 mmol). After stirring at room temperature for 16 hours, the reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a light brown oil. The oil was triturated with Et2O providing 4 mg (15%) of 1-(4-{3-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-ethanone as a pale brown solid. M+H=446.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[C:13]([CH3:15])[C:7]2[N:8]([CH3:12])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=1)=[N+]=[N-].[ClH:16].C(CCP(CCC(O)=O)CCC(O)=O)(O)=O>O1CCOCC1>[ClH:16].[CH3:12][N:8]1[C:7]2[C:13]([CH3:15])=[CH:14][C:4]([NH2:1])=[CH:5][C:6]=2[N:10]=[C:9]1[CH3:11]
Reactant: Cc1cc(N=[N+]=[N-])cc2nc(C)n(C)c12
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(N)cc2nc(C)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 200 mg (1.00 mmol) 5-azido-1,2,7-trimethyl-1H-benzimidazole, 420 mg (1.50 mmol) tris(2-carboxyethyl)phosphine-hydrochloride, 1.5 mL dioxane and 0.5 mL E-water were combined and the mixture was stirred at RT overnight. Then the reaction mixture was acidified and extracted with EtOAc. The aqueous phase was made alkaline with aqueous sodium hydroxide solution and extracted with DCM. The organic phase was dried on sodium sulphate, filtered and evaporated down. The residue was combined with ethereal hydrochloric acid and the hydrochloride that settled out as precipitate was suction filtered and dried.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=O.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.FC(F)(F)C(O)=O.[N:38]1([C:44]2[N:52]=[C:51]([C:53]3[CH:54]=[N:55][C:56]([NH2:59])=[N:57][CH:58]=3)[N:50]=[C:49]3[C:45]=2[N:46]=[C:47]([N:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[N:48]3[CH2:60][C:61]([F:64])([F:63])[F:62])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(N(CC)CC)C.CN(C)C=O>[NH2:59][C:56]1[N:57]=[CH:58][C:53]([C:51]2[N:50]=[C:49]3[C:45]([N:46]=[C:47]([N:65]4[CH2:70][CH2:69][N:68]([C:4](=[O:6])[CH2:3][C@H:2]([OH:1])[CH3:7])[CH2:67][CH2:66]4)[N:48]3[CH2:60][C:61]([F:62])([F:64])[F:63])=[C:44]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:52]=2)=[CH:54][N:55]=1
Reactant: C[C@@H](O)CC(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Reaction time: 15 h
Yield: 48.2 %

Procedure:
(R)-3-hydroxybutanoic acid (39 mg, 0.38 mmol), hydroxybenzotriazole hydrate (58 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72 mg, 0.38 mmol), dimethylformamide (5 ml), triethylamine (161 μl) were added to 5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine trifluoroacetate (200 mg, 0.29 mmol) and the resulting mixture was stirred for 15 hours. The reaction mixture was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (77 mg, 48%) as a colorless solid.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].[CH3:17][C:18]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[C:18]([Si:21]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:20])([CH3:17])[CH3:19]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C#CCCCCCCCCCCCCCO
Product: C#CCCCCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 91.9 %

Procedure:
Silylation of pentadec-14-yn-1-ol (8.80 g, 39.28 mmol) using TBDPSCl (12.92 g, 47.14 mmol) as described above gave tert-butyl(pentadec-14-ynyloxy)diphenylsilane (16.7 g, 87%) as a colorless oil. TLC: 6% EtOAc/hexanes, Rf≈0.6; 1H NMR (CDCl3, 300 MHz) δ 7.65-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.65 (t, J=7.3 Hz, 2H), 2.15-2.21 (m, 2H), 1.94 (t, J=1.9 Hz, 1H), 1.20-1.60 (m, 22H), 1.04 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH3:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH3:33])=[CH:20][CH:21]=1
Reactant: CCc1ccccc1OCC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccccc1OCCNc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2-ethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 445 (M++1)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@H:5]1[O:17][CH3:18])=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]1[O:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1CNCC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 206.4 %

Procedure:
To a stirred solution of 247A (310 mg, 1.21 mmol) in 2 mL of CH2Cl2 at room temperature was added TFA (2.00 mL, 26.0 mmoL). This mixture was stirred at room temperature for 15 min and concentrated in vacuo to give 390 mg of (3R,4R)-rel-4-azido-3-methoxypiperidine as the TFA salt. Compound 247B was prepared from this TFA salt (52.0 mg, 0.19 mmoL) in a similar process as described for 146E. It had an analytical HPLC retention time=1.97 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10–90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=409.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])[N:12]=[C:11]2[N:23](C3CCCCO3)[N:24]=[C:25]([CH3:26])[C:10]=12.Cl>O1CCCC1>[CH3:1][C:2]1([CH3:33])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])[N:12]=[C:11]2[NH:23][N:24]=[C:25]([CH3:26])[C:10]=12
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(CN3CCNCC3(C)C)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CCNCC3(C)C)c12
Yield: 56.7 %

Procedure:
130 mg 4-[4-(2,2-dimethyl-piperazin-1-ylmethyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-3-fluoro-phenol were dissolved in 5 ml dry tetrahydrofurane and 1 ml HCl (4N in 1,4-dioxane) was added. After stirring the reaction at r.t. for 60 min the volatiles were removed in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate/methanol gradient). 60 mg (23%) of the title compound were obtained.