Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](C#CC4N5C=CN=CC5=NC=4)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.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.[Cu]I>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-ethynylimidazo[1,2-a]pyridine (0.032 g, 0.22 mmol) in anhydrous DMF (1.26 mL) was added N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (prepared as in Example 3), Pd(PPh3)4 (0.013 g, 0.011 mmol), CuI (0.0032 mg, 0.0165 mmol) and DIPEA (0.064 mL, 0.44 mmol). The solution was degassed with argon for 15 minutes then stirred overnight at rt. The solvent was removed and the resultant residue was chromatographed over silica gel eluting initially with EtOAc and then with methanol/methylene chloride (5:95) to furnish the desired product: (0.07 g, 59%) MS (M+H)+542.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:19]([O:26][C:27](=[O:35])[CH2:28][C@@H:29]([NH2:34])[CH2:30][N:31]([CH3:33])[CH3:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:35])[CH2:28][C@@H:29]([NH:34][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30][N:31]([CH3:32])[CH3:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCCCCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCc1ccccc1

Procedure:
The title compound, m/e=347.4 ([M−H]−), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 8-phenyloctanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(8-phenyl-octanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:12][CH2:13][C:14](Cl)=C)=[CH:9][CH:10]=2)[O:5][C:4](=[O:18])[CH:3]=1.[CH2:19](N(CC)C1C=CC=CC=1)C>CCOCC>[CH3:1][C:2]1[C:11]2[CH:10]=[C:9]3[C:8](=[C:7]([CH3:17])[C:6]=2[O:5][C:4](=[O:18])[CH:3]=1)[O:12][C:13]([CH3:14])=[CH:19]3
Reactant: CCN(CC)c1ccccc1
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C
Solvent: CCOCC
Product: Cc1cc2cc3c(C)cc(=O)oc3c(C)c2o1
Yield: 41.6 %

Procedure:
A mixture of 4,8-dimethyl-7-(2'-chloroallyloxy)coumarin (500 mg., 1.89 m mole) and N,N-diethylaniline (5.0 ml) was protected by an "Aquasorb" (TM), brand of phosphorous pentoxide drying tube, while being heated under reflux for twenty-four hours at an oil bath temperature of 220°-225° C. Treatment of the reaction mixture as described in part 1-B gave some black, ether-insoluble material which was discarded. The desired 4,5',8-trimethylpsoralene was obtained as a tan solid (154 mg., 41.6% yield), which was recrystallized from 95% ethanol to obtain light tan needles (53 mg., 14% yield) of m.p. 233° C. (rptd: m.p. 234° C.). Its infrared spectrum was identical to that of a commercial sample.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]2=[O:35])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([OH:6])=[O:5])[CH3:2].C(N(CC)CC)C.[C:43]([O:49][CH2:50]Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:43]([O:49][CH2:50][CH:7]([P:4]([OH:6])([O:3][CH2:1][CH3:2])=[O:5])[C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]2=[O:35])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOP(=O)(O)CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(O)C(COC(=O)C(C)(C)C)C1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1

Procedure:
0.6 g of tert-butyl (3S)-3-(1-ethylphosphono-methylcyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 17) were reacted with 1.73 ml of triethylamine, 0.86 ml of pivaloyloxymethyl chloride and 0.1 g of dimethylaminopyridine according to the method indicated in Example 6. After chromatography on silica gel (eluent: ethyl acetate), 392 mg of the title compound were obtained as a viscous resin, IR=1740, 1650 cm-1 (CH2Cl2); [α]D20 =-122.90° (c=0.257 in methanol).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9])=C.Cl.[OH-].[Na+]>CCO.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc12
Yield: 96 %

Procedure:
A solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (2-vinyloxyethoxy) amide (11a) (55.4 mg, 0.114 mmol) and aqueous HCl (1 M, 0.23 mL) in EtOH (3 mL) was stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 6-7 with aqueous NaOH (2 N). The reaction was diluted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 50.2 mg (96% yield) of the desired product (12a). MS APCI (−) m/z 456, 458 (M+, Br, Cl pattern) detected: 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 4.01 (t, 2H), 3.74 (t, 2H), 2.60 (s, 3H): 19F NMR (376 MHz, CD3OD) −140.85 (s, 1F).
Reaction SMILES: [ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH:18]C(OC(C)(C)C)=O)[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC.CO>[ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 N solution of HCl in ether (15 ml) was added in stirring solution of compound 5 (10.0 g, 21.9 mmol) in methanol at 0° C. The mixture was allowed to warm to room temperature gradually and continue stirred for 2 hr. Solvent was evaporated under reduced pressure, and the residue was treated with anhydrous ether (120 mL) to precipitate the product 6. The precipitated product was washed with ether (50 mL×2) afforded the titled compound as white solid. [α]D25−28.19°; 1H NMR (500 MHz, DMSO-d6): δ 8.40 (bs, 2H, D2O exchange, NH2), 7.88 (m, 4H), 7.64 (m, 2H), 7.45 (m, 4H), 5.48 (m, 2H), 5.07 (m, 1H), 3.96 (m, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 2.47 and 2.39 (m, 1H), 1.63 (m, 1H); HR-MS Calcd. For (C20H21NO5)+ 355.1420. found 335.1293.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([CH2:31][OH:32])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.Cl>C1COCC1.C(OCC)(=O)C>[OH:32][CH2:31][C:30]1[N:17]2[C:18]([C:19]3[CH:20]=[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=4)=[N:13][C:14]=3[CH:15]=[CH:16]2)=[N:28][N:29]=1
Reactant: OCc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 14-1 (2.1 g, 4.9 mMol) in THF (50 mL) was added 1N HCl (50 mL). After stirring at room temperature for 30 minutes, the reaction was diluted with ethyl acetate and washed twice with water, followed by brine. The organic layer was dried with MgSO4 and Na2SO4, filtered and concentrated in vacuo to yield 14-2 as a red solid. Mass (M+1) calculated: 381.1346 observed: 381.1346.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCOC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Racemic (tetrahydrofuran-3-yl)methanamine (3.84 g, 38.0 mmol) and diisopropylethylamine (13.26 ml, 76 mmol), were dissolved in dichloromethane (100 ml) and cooled to 0° C. The mixture was treated dropwise via an addition funnel with benzyl carbonochloridate (6.19 ml, 41.8 mmol) dissolved in 30 ml dichlormethane. After the addition the cooling bath was removed and the homogeneous solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between water and ethyl acetate and the separated aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:39])[N:3]=1.C(O)(=O)C.[CH:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH:39][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(COc2cccc(N)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(COc2cccc(NCc3ccccc3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-(2-amino-6-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate (0.30 g, 0.566 mmol) in methanol (10 mL) including acetic acid (0.03 g, 0.566 mmol) was added benzaldehyde (0.08 mL, 1.133 mmol) followed by sodium cyanoborohydride (0.04 g, 0.566 mmol), and the stirring was continued at 0° C. for 3 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give tert-butyl 3-(2-amino-6-{2-(benzylamino)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate as a yellow amorphous (0.299 g, yield; 85%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([N:21]3C(=O)C4C(=CC=CC=4)C3=O)=[N:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccccc2OCc2ccccc2)n1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccn(Cc2ccccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of 2-[1-({2-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-1H-isoindole-1,3(2H)-dione (4.83 g, approx 11.8 mmol) in THF (50 ml) was added hydrazine hydrate (2.86 ml, 59 mmol) and the solution was stirred overnight at ambient temperature. A white solid was filtered off and the filtrate dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was applied to 100 g silica and purified using 0-100% ethyl acetate-cyclohexane to give the title compound as a pale yellow oil (1.66 g); LCMS: (System 3) MH+=280, tRET=0.96 min.
Reaction SMILES: O1CCCC1.Cl.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[C:16]([CH:27]=[CH:28][O:29]C)=[N:15]2)=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[C:16]([CH2:27][CH:28]=[O:29])=[N:15]2)=[CH:31][CH:32]=1
Reactant: COC=Cc1nn(Cc2ccc(OC)cc2)c2cccc(C(=O)OC)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1c(CC=O)nn2Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a −78° C. cooled suspension of (methoxymethyl)triphenylphosphonium chloride (119 g, 347 mmol) in tetrahydrofuran (1000 mL) was carefully added a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 347 mL, 347 mmol). The resulting dark red mixture was stirred at −40° C. for 30 min. To this was added a solution of methyl 3-formyl-1-(4-methoxybenzyl)-1H-indazole-4-carboxylate (45 g, 139 mmol) in tetrahydrofuran slowly and the mixture was stirred for 30 min. The reaction was quenched with sat. aqueous sodium chloride (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (4×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography (silica gel, 5 to 30% ethyl acetate in hexanes) to afford methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 82%) as a yellow oil. A mixture of tetrahydrofuran (950 mL) and 6N hydrochloric acid (30 mL) was added to methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 114.5 mmol) and the resulting biphasic mixture was heated to reflux for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (1500 mL). The organic layer was separated and washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indazole-4-carboxylate (30 g, 77%) as a yellow solid: 1H NMR δ (300 MHz, DMSO-d3) 9.78 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.2, 0.6 Hz, 1H), 7.48 (dd, J=8.7, 7.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.88-6.85 (m, 2H), 5.61 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H); MS (ESI+) m/z 339 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:31]([CH2:32][CH3:33])=[CH:30][N:29]=[C:28]([CH3:34])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:31]([CH2:32][CH3:33])=[CH:30][N:29]=[C:28]([CH3:34])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: CCc1cnc(C)cc1-c1cccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (230 mg, 72%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH2:36]([Mg]Br)[CH:37]=[CH2:38].[Cl-].[NH4+]>O1CCCC1>[OH:35][C:32]1([CH2:38][CH:37]=[CH2:36])[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: C=CC[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC1(O)CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
4′-{[5-Oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.8 g) was dissolved in tetrahydrofuran (10 mL), and allylmagnesium bromide (1.0 M diethyl ether solution, 2.1 mL) was added at −78° C. The reaction mixture was warmed to room temperature, and the mixture was stirred for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 30%).
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([OH:40])=O)[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:93][C:94]1([CH2:97][OH:98])[CH2:96][CH2:95]1>C(Cl)Cl>[C:1]([NH:14][C@H:15]([CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:38]([NH:93][C:94]1([CH2:97][OH:98])[CH2:96][CH2:95]1)=[O:40])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: NC1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl) methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hr. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (9H-fluoren-9-yl)methyl (R)-3-((R)-2-dodecanamido-3-(hexadecyloxy)propylthio)-1-(1-(hydroxymethyl)cyclopropylamino)-1-oxopropan-2-ylcarbamate.
Reaction SMILES: [Na].[CH2:2]([N:9]=[N+:10]=[N-:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]([CH2:16][CH2:17][CH:18](C(OCC)=O)[C:19](OCC)=[O:20])([O:14]C)=[O:13]>C(O)C>[CH2:2]([N:9]1[C:19]([OH:20])=[C:18]([CH2:17][CH2:16][C:12]([OH:14])=[O:13])[N:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCC(=O)OC)C(=O)OCC
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCc1nnn(Cc2ccccc2)c1O

Procedure:
To a solution of 1.725 g. (75 mmol.) of sodium in 50 ml. of absolute ethanol is added 6.0 g. (45 mmol.) of benzylazide and 12.3 g. (50 mmol.) of diethyl 2-(carbomethoxyethyl)malonate. The reaction mixture is refluxed for 12 hours, then cooled and evaporated to dryness. Water (100 ml.) is added and the mixture is heated while maintaining the pH at 12. The aqueous mixture is extracted with ethyl acetate and the aqueous phase is acidified with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is evaporated to dryness to give 1-benzyl-4-(2-carboxyethyl)-5-hydroxy-1,2,3-triazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].CCOCC.[OH-].[Na+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: N#Cc1cccc(CCCO)c1
Yield: 96.9 %

Procedure:
Into an oven-dried 500 ml flask with 2-neck adapter and stirring bar, 12.9 g of 3-(3-cyanophenyl)propanoic acid (the product of step (a)) was placed. The system was flushed with argon gas; then 84 ml tetrahydrofuran was added. The resulting mixture was stirred until the acid was dissolved. After cooling for about ten minutes with an ice bath, 88 ml borane-tetrahydrofuran was added in two 44 ml portions over a 20 minute period. The reaction mixture was stirred for 20 minutes in an ice bath and then quenched by the addition of about 17 ml water dropwise. The mixture was stripped to give an oil with white crystals. Ether (200 ml) and a solution of 8.8 g (0.22 mole) sodium hydroxide in 150 ml water were added. The organic phase was separated. The aqueous layer was extracted with an additional 35 ml ether. The combined ether extracts were dried over sodium sulfate, filtered, and stripped. The resulting oil was distilled in a Kugelrohr apparatus, the fraction bpt. 95°-110° C. was collected to give 11.5 g of the above-identified product.