Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:18])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:41]S(C2C=CC=CC=2)(=O)=O)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:29]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:28]=1)#[N:26]>O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:41][C:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]=2[NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]([F:18])[F:3])[CH:6]=2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:29]([S:51]([CH3:54])(=[O:52])=[O:53])[CH:28]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)F)c2)CCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 106 mg, 2.67 mmol) is added in portions to a mixture of 3-(3-(difluoromethyl)phenylamino)cyclopent-2-enone (intermediate 5, 595 mg, 2.66 mmol) and 2-methyltetrahydrofuran (20 mL). After 2 h tert-butyl (4-cyano-2-(methyl-sulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 1.00 g, 2.20 mmol) is added, and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with 2-methyltetrahydrofuran. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 665 mg; ESI mass spectrum [M+H]+=532; Retention time HPLC: 1.13 min (Z018_S04).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][O:52][CH:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1.C(O)(=O)C>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:56]3[CH2:57][CH2:58][CH:53]([O:52][CH3:51])[CH2:54][CH2:55]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCC(OC)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (400 mg, 0.78 mmol) (example 1), sodium triacetoxyborohydride (260 mg, 1.23 mmol), 4-methoxycyclohexanone (100 mg, 0.78 mmol) (J. Am. Chem. Soc. 5190, 89, 1967) and acetic acid (56 mg, 0.93 mmol) in tetrahydrofuran (30 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (94:6:0.3) to give the title compound as a mixture (3:2 ratio) of diastereoisomers (118 mg) as a foam. MS: 603 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].FC(F)(F)C(O)=O.[F:64][C:65]1[CH:66]=[N:67][C:68]2[NH:69][C:70]3[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=3)[CH2:75][CH2:76][C:77]3[CH:85]=[C:81]([NH:82][C:83]=1[N:84]=2)[CH:80]=[CH:79][C:78]=3[NH2:86]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[F:64][C:65]1[CH:66]=[N:67][C:68]2[NH:69][C:70]3[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=3)[CH2:75][CH2:76][C:77]3[CH:85]=[C:81]([NH:82][C:83]=1[N:84]=2)[CH:80]=[CH:79][C:78]=3[NH:86][C:16](=[O:18])[CH2:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]([C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[O:8])[CH2:14][CH2:13]1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(F)c(n1)N2
Reactant: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(F)c(n3)N4)CC2)no1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A solution of {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetic acid (2.0 mg, 0.0079 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (8.1 mg, 0.021 mmol) in N,N-dimethylformamide (0.1 mL) and N,N-diisopropylethylamine (3.2 uL) was stirred for 15 minutes. A solution of 6-fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) (2.5 mg, 0.0078 mmol) in N,N-dimethylformamide (0.04 mL) and was added to the previous solution and stirred overnight. The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (0.5 mg, 14%). LCMS for C29H30FN8O3 (M+H)+: m/z=557.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][NH2:33]>ClCCl.[OH-].[Na+]>[NH:32]([C:15]([C:14]1[CH:18]=[CH:19][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=1)=[O:16])[NH2:33]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-((tert-butoxycarbonyl)amino)ethyl)benzoic acid (3.364 g, 12.7 mmol) in anhydrous dichloromethane (60 mL) was added carbonyldiimidazole (2.264 g, 13.97 mmol). The reaction mixture was stirred at room temperature for 45 minutes before anhydrous hydrazine (1 ml) was added and the mixture stirred at room temperature for another 16 hours. Evaporation to dryness gave a white solid that was stirred in 1.5N sodium hydroxide (200 mL) for 30 minutes before being filtered off and washed with water (2×100 mL). Drying under vacuum gave tert-butyl 4-(hydrazinecarbonyl)phenethylcarbamate as a white powder (2.847 g). 400 MHz 1H NMR (DMSO-d6) δ: 9.69 (s, 1H), 7.74 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 6.9 (t, J=5.2 Hz, 1H), 4.45 (s, 2H), 3.15 (m, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.36 (s, 9H). LCMS [M+]: 279.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](O)=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].CS(Cl)(=O)=O.[N:31]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:31])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Cl)ccc1OCC(C)C)c1ccc(C(=O)O)nn1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Product: CCN(Cc1cc(Cl)ccc1OCC(C)C)c1ccc(C#N)nn1
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
6-[N-(5-Chloro-2-(2-methylpropoxy )benzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 10) (2.0 g) was dissolved in pyridine (30 ml) under argon and cooled to 4° C. Methanesulphonyl chloride (0.75 ml, 9.7 mmol) was added to the mixture which was stirred at 4° C. for 1.5 hours to give a dark purple solution. Ammonia gas was then bubbled through the solution for 2 minutes to give a dark red solution (exotherm to +15° C.) and the solution evaporated under reduced pressure. The residue was dissolved in pyridine (30 ml) and cooled under argon to 4° C. Methanesulphonyl chloride (5.1 ml, 66 mmol) was then added dropwise (exotherm to 10° C.) and the resultant brown suspension stirred at ambient temperature overnight. The brown solution was then evaporated and the residue partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2N HCl/saturated aqueous ammonium chloride (×2), saturated aqueous sodium bicarbonate (×1) and brine (×1), dried over Na2SO4, filtered and evaporated. The title product was isolated by column chromatography using 20% ethyl acetate/isohexane as eluant (1.18 g, 62.2%). [OPPI 14: 396-9 (1982)].
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:19])(C(Cl)(Cl)Cl)[C:8]2C=CC(Cl)=CC=2)=[CH:5]C=[C:3](Cl)[CH:2]=1.C=CC=C>>[CH2:6]=[CH:1][CH:2]=[CH2:3].[O:19]1[CH2:8][CH:7]1[CH:6]=[CH2:5]
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Agent: C=CC=C
Product: C=CC1CO1

Procedure:
CPCA is derived from 1,3-butadiene by a sequence of four reactions. Monoepoxidation of 1,3-butadiene produces 3,4-epoxy-1-butene (EPB) as described in U.S. Pat. Nos. 4,897,498 and 4,950,773. This epoxide is isomerized to 2,5-DHF (U.S. Pat. Nos. 5,082,956 and 5,315,019) which is isomerized to 2,3-DHF (U.S. Pat. Nos. 5,254,701 and 5,536,851). Finally, 2,3-DHF is isomerized to CPCA (C. L. Wilson, J. Amer. Chem. Soc., 69, 3002 (1947) and U.S. Pat. No. 5,502,257).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[N:8][CH:9]=1.[CH3:17]I>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:17])[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: Brc1cncc(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 143.3 %

Procedure:
NaH (17 mg, 0.71 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (1.2 mL) was added. The slurry was cooled to 0° C. and compound 10 (164 mg, 0.653 mmol, 1.00 eq) was added as a solution in THF (1.2 mL). After stirring at 0° C. for 30 minutes methyl iodide (44.8 μL, 0.708 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 248 mg (93%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.62 (s, 2H), 8.35 (d, J=2.4 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.78 (t, J=2.2 Hz, 1H), 3.36 (s, 3H); [M+1]+: 265.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(O)c2)CC1
Product: COCCOc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield (355 mg, colorless syrup) from tert-butyl 4-(3-hydroxyphenoxy)piperidine-1-carboxylate (300 mg, 1.02 mmol) and 1-bromo-2-methoxyethane (171 mg, 1.23 mmol) at a reaction temperature of 60° C. by the similar manner in Step-1 of Intermediate-2.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C@H:3]2[CH2:6][NH:7][CH2:8][C@@H:2]12.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.CC(C)([O-])C.[Na+].C(OCC)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:7]2[CH2:6][C@H:3]3[C@H:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3cccnc3)C[C@H]21
Temperature: 80 °C
Yield: 91.1 %

Procedure:
The product from Example 15E (0.71 g, 3.30 mmol) in toluene (33 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, available from Alfa Aesar) (61 mg, 0.10 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, available from Strem Chemicals) (83 mg, 0.10 mmol), 3-bromopyridine (available from Aldrich Chemical Co.,) (0.58 g, 3.70 mmol), and sodium tert-butoxide (available from Aldrich Chemical Co.,) (0.54 g, 5.60 mmol). After heating at 80° C. for 16 hours, the mixture was poured into diethyl ether (100 mL), washed with brine (100 mL), dried(MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 5% MeOH/CH2Cl2) to provide the title compound as a yellow oil (0.87 g, 91% yield). MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:34]=[CH:35][N:36]([CH2:39][C:40]#[CH:41])[C:37]=1[Cl:38]>N(CC)CC.CN(C=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][N:36]4[C:37]([Cl:38])=[C:33]([Cl:32])[N:34]=[CH:35]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCn1cnc(Cl)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCn3cnc(Cl)c3Cl)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.1 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) and anhydrous DMF (10 mL) is added 4,5-dichloro-1-prop-2-ynylimidazole (104.8 mg). The reaction is sonicated and stirred at room temperature for 2 days. The reaction is condensed to afford a residue. The residue is adsorbed onto silica and chromatographed (eluant 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined and condensed to afford 20 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:33]1([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH2:45][NH:46][CH2:47][CH2:48][CH3:49])[CH:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:46]([CH2:45][C:41]2[CH:40]=[C:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:44]=[CH:43][N:42]=2)[CH2:47][CH2:48][CH3:49])=[O:9])[N:4]=[CH:3]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CCCNCc1cc(-c2ccccc2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(Cc1cc(-c2ccccc2)ccn1)C(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
To a solution of methyl-1H-imidazole-4-carboxylic acid (53 mg) in dimethylformamide (1 mL) was added 1-hydroxybenzotriazole hydrate (HOBT.H2O) (64 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (81 mg) and the mixture was stirred at room temperature for 10 min. A solution of N-[(4-phenylpyridin-2-yl)methyl]propan-1-amine (80 mg) in dimethylformamide (2 mL) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure and then saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-82:18) and (the same column, chloroform:methanol=100:0-90:10) to afford the title compound (33 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:4].I[CH2:30][CH3:31].[NH4+].[Cl-]>CCCCCC>[CH2:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:3][CH3:4])[C:6]=1[C:13]1[CH:14]=[C:15]([O:27][CH3:28])[C:16]([CH:19]([O:20][CH2:30][CH3:31])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][N:18]=1)[CH3:12]
Reactant: CCI
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)c2ccccc2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Product: CCOC(c1ccccc1)c1cnc(-c2c(CC)cccc2CC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (60% in mineral oil, 8 mg) is added to a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-phenyl-methanol (18 mg) in DIM (1 mL). The resulting mixture is stirred at room temperature for 15 minutes. The mixture is then treated with iodoethane (20 mg) and stirred at the same temperature for 1 hour. Aqueous NH4Cl solution (5 mL) and hexane (5 mL) are added to the mixture. The organic layer is separated, dried, and concentrated in vacuo. The crude product is purified by PTLC (4:1 hexane/EtOAc) to give 2-(2,6-diethyl-phenyl)-5-(ethoxy-phenyl-methyl)-4-methoxy-pyridine. 1H NMR (CDCl3) 8.66 (s, 1H), 7.45 (d, 2H), 7.35 (t, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 6.71 (s, 1H), 5.74 (s, 1H), 3.80 (s, 3H), 3.56 (q, 2H), 2.33 (m, 4H), 1.27 (t, 3H), 1.05 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:26][C:25](=[N:27][NH2:28])[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:37](OCC)(OCC)OCC>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:20][C:21]4[N:26]5[CH:37]=[N:28][N:27]=[C:25]5[CH2:24][O:23][C:22]=4[N:29]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=NN)CO4)cc2)CCC1
Reactant: CCOC(OCC)OCC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3cnnc3CO4)cc2)CCC1
Yield: 15 %

Procedure:
A solution of tert-butyl(1-(4-(2-hydrazono-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) in triethyl orthoformate (1 mL) was heated at 150° C. for 10 min under microwave irradiation. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 2% MeOH in dichloromethane) to give the title compound (3 mg, 15%). 1H NMR (500 MHz, CDCl3): 8.68 (1H, s), 7.75 (1H, s), 7.34-7.26 (7H, m), 7.22-7.20 (2H,m), 5.70 (2H, s), 5.02 (1H, br s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1ccncc1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)c3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 86b) and isonicotinic acid as brown solid (41%). MS 409 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:28])[CH:21]=[CH:20]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(=O)ON3C(=O)CCC3=O)ccc2c1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a susupension of N-hydroxysuccinimide (0.56 g) and 6-heptyloxy -2-naphthoic acid (1.39 g) in methylene chloride (42 ml) was added 1-ethyl -3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.21 g) and stirred for 3 hours at room temparature. The reaction mixture was added to water (100 ml). The organic layer was separated and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give succinimido 6-heptyloxy -2-naphthoate (1.48 g).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[B:30](OC)([O:33]C)[O:31]C.Cl>C1COCC1>[F:16][C:17]1[C:18]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[C:19]([F:23])[CH:20]=[CH:21][C:22]=1[B:30]([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: Fc1cccc(F)c1-c1ccncc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (3.10 ml, 18.4 mmol) in THF (80 ml) was cooled to −20° C., then treated with a 2.5 M solution of butyllithium in hexanes (7.03 ml, 17.6 mmol). After stirring at −20° C. for 10 min, the mixture was cooled to −78° C. and treated with a solution of 4-(2,6-difluorophenyl)pyridine (3.20 g, 16.7 mmol) in THF (20 ml). The mixture was stirred at −78° C. for 1.5 h before adding trimethyl borate (3.78 ml, 33.5 mmol). The mixture was allowed to warm to room temperature before adding 5 N aqueous HCl (20 ml). After stirring for 12 h, the solvent was removed in vacuo and the residue was partitioned between 1 N aqueous HCl (100 ml) and diethyl ether (100 ml). The organic layer was then extracted with 1 N aqueous NaOH and the aqueous layer was acidified to pH 8 with 5 N aqueous HCl. The resulting solid was collected by filtration, washed with water and dried to afford 3.20 g (81%) of 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid as a white solid: MS (ES+) m/z 235 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2ccc(N)cc2CC1
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Into a Parr hydrogenation bottle, the product from step (a) (17 g) dissolved in EtOAc (200 ml) was added. To the Ar purged bottle 10% Pd—C (1.7 g) was added. The reaction mixture was shaken under hydrogen (50 psi) for 3 hours. The reaction mixture was filtered through celite and solvent evaporated in vacuo to give the sub-title compound as an off-white solid (12.9 g). 1H NMR (300 MHz, CDCl3) δ 6.77 (d, J=7.8 Hz, 1H); 6.35 (s, 1H); 6.30 (d, J=8.1 Hz, 1H); 4.84 (s, 2H); 4.06 (q, J=6.9 Hz, 2H); 3.43 (bs, 4H); 2.66 (bs, 4H); 1.19 (t, 7.2 Hz, 3H). MS: ESI (positive): 235 (M+H).