Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C([N:54]1[CH2:59][CH2:58][NH:57][C@@H:56]([CH3:60])[CH2:55]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:57]5[CH2:58][CH2:59][NH:54][CH2:55][C@H:56]5[CH3:60])[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCNC[C@H]3C)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), (S)-4-N-Boc-2-methyl piperazine (17.69 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents) with eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(6-methyl-3′-{[(2R)-2-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide as a solid (26 mg, 41.6%). LC-MS m/z 707 (M+H)+, 0.77 min (ret time).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=2)=[CH:3][CH:4]=1)[OH:13]
Reactant: COc1cccc(B(O)O)c1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2ccc([C@@H](O)C(F)(F)F)cc2)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a stirred solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (2, 69 g, 0.27 mol, >99% ee), 3-methoxy phenylboronic acid (Matrix, 51 g, 0.34 mol, 97% purity), and bis(triphenylphosphine)palladium(II) dichloride (0.95 g, 0.5% mol) in ethanol (560 ml) was added a solution of potassium carbonate (112 g, 0.81 mol) in water (140 ml) under nitrogen. The resulting mixture was heated at 75° C. for 1 hour and deemed complete by GC-MS or TLC. After reaction mixture was cooled to 40° C., it was filtered through a pad of Celite, washed with methanol (3×100 ml). The filtrate was diluted with 100 ml of water and concentrated. The resulting syrup was dissolved in 700 ml of ethyl acetate and washed with 1 N sodium hydroxide (2×100 ml), water (2×100 ml) and brine (1×100 ml). The organic layer was heated with activated carbon (14 g) and Hyflo Super Cel (14 g) at 60° C. for 1 hours. This mixture was filtered hot and washed with ethyl acetate (100 ml) and then concentrated to a syrup. This syrup was immediately dissolved in 1% ethyl acetate/heptane (700 ml) and stirred for 4 hours. The resulting slurry was filtered and dried to give the titled compound as a white crystalline solid (3, 68 g, 89% yield, >99% ee)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: Brc1nccs1
Reactant: CN1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Product: CN1CCC[C@H]1COc1nccs1
Yield: 73.8 %

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidine methanol (484 mg, 4.2 mmol) was reacted with NaH ((80% dispersion in mineral oil) 0.164 g 5.46 mmol) and 2-bromothiazole (0.417 g, 4.62 mmol) according to the procedure outlined in Example 3a to afford after column chromatography eluting with (10% MeOH/CHCl3 +1% NH3) (616.2 mg, 3.1 mmol, 74% yield) of 2-(1-methyl-2-(S)-pyrrolidinylmethoxy)-thiazole. The pure base was then converted to its hydrochloride salt by treating the amine (109.4 mg, 0.552 mmol) with a saturated solution of HCl in Et2O dropwise with stirring until no more precipitate formation was observed. This afforded 21.2 mg, 0.09 mmol, 16% of the title compound. mp=99°C. [α]D20 =+2.86° (c=0.021, MeOH). MS (DCI/NH3) m/e 199 (M+H)+. 1H NMR (CD30D, 300 Mz) δ: 7.18 (d, J=4.04 Hz, 1H), 6.99 (d, J=4.04 Hz, 1H), 4.85 (dd, J=12.50, 3.31 Hz, 1H), 4.65 (dd, J=12.5, 6.62 Hz, 1H), 4.09-3.85 (m, 1H), 3.85-3.65 (m, 1H), 3.03 (br s, 3H), 2.45-2.3 (m, 1H), 2.3-1.95 (m, 3H). Analysis calculated for C9H15N2OSClΩ0.6 H2OΩ0.1Et2O: C, 44.63; H, 6.85; N, 11.07; Found: C, 44.68; H, 6.46; N, 10.68.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(C)nc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(C=O)nc12
Yield: 89.5 %

Procedure:
To a solution of (R)-6-fluoro-8-(1-methoxypropan-2-yloxy)-2-methylquinoline (0.70 g, 2.8 mmol) in dioxane (55 mL) and water (0.55 mL) was added selenium dioxide (0.38 g, 3.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to afford the title compound (0.66 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cn2cc(N)ccc2n1
Product: CCOC(=O)c1cn2cc(NC(C)=O)ccc2n1

Procedure:
A suspension of 0.2 g of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (Heterocycles, 38(7), 1527 (1994)) in 1 ml of acetic anhydride is heated at reflux for 45 minutes. The reaction mixture is concentrated under reduced pressure; the residue is taken up in water and basified by addition of a 1N sodium hydroxide solution. The solid is filtered off and dried to give 150 mg of ethyl 6-acetamidoimidazo[1,2-a]pyridine-2-carboxylate in the form of an ecru solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1.C(#N)C.[OH:24]O>CO.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][C:2]1([CH3:20])[CH:7]2[O:24][C:6]2([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: OO
Reactant: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2C2(c3ccccn3)OC12

Procedure:
3 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile and 420 mg of sodium tungstate were heated in 30 ml of methanol and 30 ml of acetonitrile at 50° C. and 12 ml of 30% (w/v) hydrogen peroxide were added. After heating overnight the mixture was evaporated and the residue was taken up in dichloromethane and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3 and 1:2) for the elution to give 440 mg of 1a,7b-dihydro-2,2-dimethyl-7b-(2-pyridyl)-2H-oxireno[c][1]benzopyran-6-carbonitrile which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:27]C=2C=1.N>CN(C=O)C.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10]([NH2:27])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(N)=O
Reaction time: 0.5 h

Procedure:
To a solution of above mentioned (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g, 4.36 mmol) in DMF (10 ml) was added EDC (1.0 g, 5.24 mmol) and HOBt.H2O (367 mg, 2.4 mmol) at room temperature, 20 min later, it was added ammonia in (7N, 0.6 mL, 4 mmol) at room temperature. After stirring for 30 min, it was diluted with water and EtOAc, organic layer was separated and washed with Sat. NaHCO3, brine, dried and concentrated to give (R)-tert-butyl-1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (750 mg) as crude oil, which was treated with 4N HCl in Dioxane (5 mL). 30 min later, it was concentrated to give (R)-2-amino-2-cyclopropylacetamide hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3c(C)cccc3c(Oc3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-5-methyl-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][NH:8][CH2:9][CH2:10][C:2]=12.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[O:22]>C(#N)C.C(Cl)Cl>[CH:29]1([N:26]2[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH2:20][N:8]3[CH2:9][CH2:10][C:2]4[C:3](=[N:4][CH:5]=[CH:6][N:1]=4)[CH2:7]3)[CH2:24][CH2:25]2)[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: c1cnc2c(n1)CCNC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(CN1CCc2nccnc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (70 mg, 0.518 mmol), NaI (50 mg, 0.333 mmol), and K2CO3 (200 mg, 1.45 mmol) in acetonitrile is added 2-chloro-1-(4-cyclobutyl-piperazin-1-yl)-ethanone (112 mg, 0.518 mmol). The mixture is stirred overnight at rt, diluted with DCM (20 mL) and filtered through Celite. The filtrate is evaporated and the crude product is purified by silica gel chromatography eluting with EtOAc/MeOH/NEt3 (95:5:5) to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 8.35 (2H, dd), 3.85 (2H, s), 3.70-3.66 (m, 4H), 3.46 (2H, s), 3.09 (2H, t), 2.96 (2H, t), 2.75 (1H, m), 2.37-2.34 (4H, m), 2.09-1.67 (m, 6H); MS (+VE) m/z 316.21 (M++1).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]3[O:26][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 30.7 mg (0.295 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 47 mg (39% of theory).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)[CH3:3].[ClH:21]>O1CCOCC1>[ClH:21].[ClH:21].[CH3:1][N:2]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl 4-((dimethylamino)methyl)phenethylcarbamate (0.14 g, 0.50 mmol) in dioxane (1 mL) at ambient temperature was added a 4M solution of hydrogen chloride in dioxane (4 mL). The resulting solution was stirred at ambient temperature for 30 minutes, then concentrated to afford 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride as a white solid (0.12 g, 98% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[C:25](=O)([O:28]C)[O:26][CH3:27]>>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:25]([O:26][CH3:27])=[O:28])[C:17](=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccc(OCc3ccccc3)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCCc2ccc(OCc3ccccc3)cc2C1=O
Temperature: 110 °C

Procedure:
To 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.72 g) dissolved in dimethyl carbonate (30 ml) was added sodium methoxide (2.70 g, 50.0 mmol), and the resulting mixture was stirred at reflux with heating (110° C.) for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (60 ml) under ice cooling and was concentrated under reduced pressure to remove the organic solvent, and the aqueous layer was then extracted with ethyl acetate (30 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 40 g, ethyl acetate/hexane=1/30). The objective fractions were concentrated under reduced pressure to obtain methyl 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.88 g, 8.88 mmol).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[C:25]([C:26]([N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH:38]5[CH2:40][CH2:39]5)[CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][C:13]=2[Cl:41])=[CH:6][C:5]=1Cl.COC(=O)C1C=CC(C#CC2C=C(Cl)C(OC3C(C(N4C5C(=CC=CC=5)N(C5CC5)CC4)=O)=CC=CN=3)=CC=2Cl)=CC=1>>[Cl:41][C:13]1[CH:14]=[C:15]([O:19][C:20]2[C:25]([C:26]([N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH:38]4[CH2:40][CH2:39]4)[CH2:30][CH2:29]3)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:16]([Cl:18])=[CH:17][C:12]=1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:43])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1Cl
Agent: COC(=O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1
Product: O=C(O)c1ccc(CCc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 168 replacing 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenylethynyl}-benzoic acid methyl ester with 4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenylethynyl}-benzoic acid methyl ester. MS (ISP): 588.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.4 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.310 g, 1.1 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (1.0 mL, 7 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Heptanoyl chloride (800 μm, 5.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and loaded onto preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform:acetone (80:20). The product was scraped from the preparative plate (Rf 0.5) and eluted from the silica gel with ethanol. After evaporation of the solvent the product was further purified on a Chromatotron (2 mm silica gel plate) with a mixture of hexane:acetone (80:20). Lyophilization afforded 0.227 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(heptanoyloxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (51% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(CNc2ccc(C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCOc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 5 g. of ethyl p-[p-(heptyloxy)benzyl]amino benzoate (prepared as described in Example 54), 1.51 g. of potassium hydroxide and 50 ml. of 95% ethanol is refluxed for 5 hours. Concentrated hydrochloric acid is added and the mixture diluted with 150 ml. of water. Chilling and filtering gives crystals which are recrystallized from ethanol to give white crystals, m.p. 148°-152.5° C.
Reaction SMILES: [C:1](#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+]>O>[CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN
Reaction time: 0.25 h
Yield: 94 %

Procedure:
300 g of stearonitrile were fed into a 1 liter autoclave and then 3 g of Catalyst A, 12 g of water and 1 g of 48% sodium hydroxide were put thereinto. After purging with nitrogen gas, the reaction was carried out under the hydrogen pressure of 2.0 MpaG at the reaction temperature of 120° C. The reaction-finishing point was determined at the point where the hydrogen gas was no longer absorbed. The reaction system was aged further for 15 minutes. Absorption of hydrogen gas proceeded smoothly and the absorption was completed in 0.8 hour. After finish of the reaction and aging, the reaction product was taken out from the reactor and the catalyst was removed off. Then, the reaction product was distilled and purified under 0.27 kPa at 220° C. Stearylamine was obtained with yield of 94%.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[O:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][C:76]2[CH:83]=[CH:82][C:79]([CH:80]=O)=[CH:78][CH:77]=2)[CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:80]([C:79]3[CH:78]=[CH:77][C:76]([O:75][CH2:74][CH2:73][N:70]4[CH2:69][CH2:68][O:67][CH2:72][CH2:71]4)=[CH:83][CH:82]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 18.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(2-morpholinoethoxy)benzaldehyde (1.2 eq, 0.091 mmol, 22 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (8 mg, 19%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (t, J=4.0 Hz, 4H, piperazine N(CH2)2), 2.72 (t, J=5.7 Hz, 2H, PhOCH2CH2), 3.30 (hidden by DMSO water peak, 4H, morpholine N(CH2)2), 3.59 (t, J=4.6 Hz, 4H, morpholine O(CH2)2), 3.61 (s, 2H, NCH2), 3.65 (s, br, 4H, piperazine N(CH2)2), 4.17 (q, J=5.8 Hz, PhOCH2CH2), 7.10 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (ddd, J=7.6, 4.8, 0.4 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.8 Hz, pyridine H-4), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.7 Hz, 1H, pyridine H-2), 13.39 (s, br, 1H, imidazo[4,5-b]pyridine NH);