Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+].I[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:45])=[O:44])C(OC(C)(C)C)=O)[CH:33]=2)[N:28](C(OC(C)(C)C)=O)[N:27]=1>CN(C)C=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:44])=[O:45])[CH:33]=2)[NH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 122 °C
Yield: 66.3 %

Procedure:
N-[3-(1H-Indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 158.1 mg of N-tert-butoxycarbonylindole-2-boronic acid and 360 μl of a saturated sodium hydrogencarbonate solution and then 48.2 mg of tetrakis(triphenyl-phosphine)palladium[0] are added to a solution of 101.9 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonylbenzenesulfonylamino)indazole-1-carboxylate in 4.5 ml of dimethylformamide. The suspension is heated in the region of 122° C. for 16 hours. After cooling to a temperature in the region of 20° C., the catalyst is filtered through a bed of Celite® 535, and the filtrate is concentrated to dryness under reduced pressure. The reaction crude is purified by preparative HPLS chromatography coupled to a mass detector (LC/MS, conditions A). The fractions containing the expected product are pooled and concentrated. 43.8 mg of N-[3-(1H-indol-2-yl)-1H-indazol-5-yl]benzenesulfonamide are obtained in the form of the trifluoroacetate salt (LC/MS analysis: Tr=3.49 minutes; [M+H]+=389.13).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].Cl.[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH2:24])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([C:13]1[N:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH3:16]
Reactant: CCOC(=O)CN
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CC(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.8 %

Procedure:
A neat mixture of N-(4-chloroquinolin-3-yl)butanamide (5.0 g, 20 mmol) and glycine ethyl ester hydrochloride (10.0 g, 72 mmol) was heated gently with a heat gun until the solids melted. The reaction was followed by LC/MS, and heat was applied briefly twice more until no starting material remained. Dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (50 mL) were added, and the resulting mixture was stirred until all solids were dissolved. The aqueous layer was separated and extracted with dichloromethane (2×50 mL), and the combined organic fractions were washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and water, dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was (3.6 g) was dissolved in hot toluene (150 mL), and pyridinium tosylate (100 mg) was added. The reaction was heated at reflux under a Dean-Stark trap for one hour, allowed to stand at ambient temperature for three days, heated at reflux for two hours, cooled to ambient temperature, and diluted with dichloromethane (150 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (2×35 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 3.2 g of ethyl (2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)acetate as a light brown solid.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][CH:10]([CH2:12][C@@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14](ON1C(=O)CCC1=O)=[O:15])[CH3:11].N(CC)(CC)CC>Cl.CN(C=O)C>[NH:24]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@@H:13]([C:14]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:15])[CH2:12][CH:10]([CH3:11])[CH3:9]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 58.3 %

Procedure:
Proline (0.842 g, 7.31 mmoles), in its HCl salt form, is dissolved in DMF and stirred with Boc-D-Leu-OSU (2.4 g, 7.31 mmoles) and (C2H5)3N (1.02 ml, 7.31 mmoles), prepared in Step C above, at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated under vacuum to dryness. The residue is dissolved in ethyl acetate washed with 0.1 N HCl, and then washed twice with H2O. The organic layer is dried over anhydrous Na2SO4 and the solvent removed by evaporation. The crude product is purified by silica gel column, yielding 1.4 g of pure Boc-D-Leu-Pro-OH.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)[C:30]=3[C:22]=2[CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=4)[C:30]=3[C:22]=2[CH:21]=1)=[O:6]
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Cl)c(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(S(C)(=O)=O)cc3)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a mixture of 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid (0.9 g, 0.0035 mol), the title compound of Example 92 (0.0024 mol) and 1 mL of diisopropylethylamine in 25 mL of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 h. Solvent was removed and the residue was purified on preparative HPLC to give the product as a pale white solid (89% yield); mp: 194-195° C.; 1HNMR (DMSO+TFA-d, 400 MHz) δ: 10.29 (s, 1H), 8.10 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 7.43 (dd, J=2.1, 8.2 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J=2.0, 8.2 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.08 (dd, J=3.0, 8.9 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 3.89 (d, J=12.8 Hz, 2H), 3.51 (d, J=12.8 Hz, 2H), 3.23(s, 3H), 3.11 (m, 2H), 2.95 (m, 4H), 2.86 (m, 2H). The bioactivity in the IKK 2 Resin assay for the compound of Example 126 is shown in Table 2.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=O)[C:5]([OH:7])=[O:6].[NH2:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12].C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH2:3][CH:2]([CH3:9])[CH3:1])([OH:7])=[O:6]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O

Procedure:
4-Methyl-2-oxopentanoic acid (1.29 g) and L-alanyl-L-proline (0.32 g) were treated with sodium cyanoborohydride (0.32 g) as described above. A fluffy white solid, N-(1-carboxy-3-methylbutyl)-L-alanyl-L-proline, was obtained (0.40 g). A portion was purified by chromatography. The mass spectrum showed a peak at 429 (molecular ion of disilyl derivative minus methyl, 444-15). The nmr spectrum showed resonances centered at 4.4, 3.6, 2.1, 1.6, and 0.95 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Reactant: O=Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(Cc3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
80 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. To the mixture were added 73 mg of benzaldehyde, 97 mg of triacetoxy sodium borohydride and 41 mg of acetic acid, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate. Then the mixture was evaporated, and the residue was purified by NH silica gel chromatography (hexane/ethyl acetate system), to give 80 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1CC[CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.[NH:38]1CCC[C@@H]1CO>>[NH2:38][C:2](=[O:1])[CH2:3][N:4]([CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][N:29]([S:32]([CH:35]([CH3:36])[CH3:37])(=[O:33])=[O:34])[CH2:30][CH2:31]2)[CH:10]=1)[CH3:5]
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC(N)=O)c4)cc23)CC1
Yield: 53.2 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting N2-methylglycinamide (90.13 mg, 1.200 mmol) for (2R)-2-pyrrolidinylmethanol to afford 15 mg of the title compound (53.2%).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:12][C:13]([C@@H:15]1[CH2:20][C@@H:19]2[O:21][C@:18]2([CH3:22])[CH2:17][CH2:16]1)=[CH2:14]>O>[C:1]12([NH:11][C@@H:17]3[CH2:16][C@@H:15]([C:13]([CH3:14])=[CH2:12])[CH2:20][CH2:19][C@@:18]3([CH3:22])[OH:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=C(C)[C@H]1CC[C@@]2(C)O[C@H]2C1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: O
Product: C=C(C)[C@H]1CC[C@@](C)(O)[C@H](NC23CC4CC(CC(C4)C2)C3)C1
Reaction time: 744 h
Yield: 39.8 %

Procedure:
A 100-mL, single-neck flask equipped with a magnetic stirring bar and a reflux condenser fitted with a nitrogen bubbler was charged with 7.71 g (0.051 mol) of 1-adamantylamine, 22.83 g (0.150 mol) of (S)-(−)-limonene oxide, and 4.0 mL of deionized water. The mixture was heated to reflux and held there for 31 days. The reaction mixture was filtered to remove some insoluble material. The filter paper was washed with a small amount of n-heptane. Upon cooling, the filtrate solidified to a nearly completely solid mass. The solid was isolated by filtration, washed with a small amount of n-heptane, air dried, and vacuum dried at 40° C. The filtrate was cooled in a freezer to give a second crop of crystals that were isolated and dried in the same manner. The two crops of crystals were combined and recrystallized from 75 mL of n-heptane to give 6.16 g of (1R,2R,4S)-2-(1-adamantylamino)-1-methyl-4-(1-methylethenyl)cyclohexanol as a white solid, mp 94-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[O:24]1[C:28]2([CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1>>[O:27]1[C:28]2([CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:32][CH2:33]2)[O:24][CH2:25][CH2:26]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCC2(CC1)OCCO2
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC2(CC1)OCCO2

Procedure:
Batch size: 4.0 g (26.8 mmol) 3-(3-pyridyl)-acrylic acid, 5.7 g (35.2 mmol) CDI and 6.4 g (29.9 mmol) 4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-butylamine.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Fc1ccccc1F
Reactant: CCCCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
n-Butyllithium (50 cm3, 10.0M in hexanes, 0.5 mol) was added dropwise to a stirred, cooled (-78° C.) solution of 1,2-difluorobenzene (57 g, 0.5 mol) in dry THF (600 cm3) under an atmosphere of dry nitrogen. The mixture was maintained under these conditions (3 h) then a solution of pentanal (43.1 g, 0.5 mol), in dry THF (50 cm3) added dropwise at -78° C. The temperature of the reaction mixture was allowed to reach room temperature overnight. An aqueous solution of ammonium chloride (27 g in 160 cm3 water) was added and the product extracted into diethyl ether (2×150 cm3), the combined extracts washed with water (2×150 cm3) and dried (MgSO4). The solvent was removed in vacuo to give the product as a colourless oil which was purified by distillation under reduced pressure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:34])[CH2:10][C@@:11]1([C:28]2[S:29][C:30](Br)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1.[C:35](=[O:38])([O-])[O-].[Na+].[Na+]>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>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:34])[CH2:10][C@@:11]1([C:28]2[S:29][C:30]([C:21]3[CH:26]=[CH:25][C:24]([C:35]4[O:38][CH:15]=[N:14][CH:13]=4)=[CH:23][CH:22]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: O=C(C[C@]1(c2ccc(Br)s2)CCN(C(=O)c2ccccc2)CCS1(=O)=O)NOC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: O=C(C[C@]1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)c2ccccc2)CCS1(=O)=O)NOC1CCCCO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5-oxazolyl)phenylboronic acid pinacol cyclic ester obtained in Preparation 9-2) were added N-(2-tetrahydropyranyloxy)-2-[(S)-4-benzoyl-7-(5-bromo-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (1.70 g), tetrakis(triphenylphosphine)palladium(0) (103 mg) and 2M aqueous sodium carbonate solution (5 ml) and the mixture was stirred at 80° C. for 4 hours. After evaporation of solvent, ethyl acetate and water were added and the insolubles were filtered off. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (100:1 to 200:3) to give N-(2-tetrahydropyranyloxy)-2-[(S)-4-benzoyl-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide as a pale yellow amorphous powder (1.28 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[F:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]([N:15]2[CH2:16][CH:13]([F:12])[CH2:14]2)=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: FC1CNC1
Reactant: O=C(O)c1ncc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ncc(F)cc1F)N1CC(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 3,5-difluoropicolinic acid (16.40 g, 103.1 mmol), 3-fluoroazetidine (8.59 g, 114 mmol) and triethylamine (27.70 ml, 199.0 mmol) in 100 mL of DMF was added HATU (45.40 g, 119.0 mmol). The mixture was stirred at room temperature for 3 hr, quenched with water, extracted with 3×EtOAc, The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a yellow solid (11.49 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=2.53 Hz, 1 H) 7.31-7.46 (m, 1 H) 5.27-5.52 (m, 1 H) 4.62-4.79 (m, 1 H) 4.42-4.59 (m, 2 H) 4.22-4.38 (m, 1 H); MS for C9H7F3N2O m/z 217.00 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:3]=1[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][CH3:16])[N:11]([CH2:17][C:18]([O:20]CC)=[O:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[C:18]([CH2:17][N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:4][C:3]3[C:23]([Cl:47])=[CH:24][CH:25]=[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]4[CH:35]=[CH:36][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:38][CH:39]=4)[C:2]=3[Cl:1])[C:14]=2[N:13]=[C:12]1[CH2:15][CH3:16])([OH:20])=[O:19]
Reactant: CCOC(=O)Cn1c(CC)nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.2 %

Procedure:
To a solution of 4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-1-ethoxycarbonylmethyl-2-ethyl-1H-benzimidazole (270 mg) in ethanol (3 ml) was added 1N sodium hydroxide solution (0.44 ml), and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was acidified with 1N hydrochloric acid, and the solvent was removed in vacuo. The residue was pulverized with 99% acetonitrile to give 1-carboxymethyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2-ethyl-1H-benzimidazole (280 mg) as pale yellow solid.
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[C:8]12[C:17](=[O:18])O[C:14](=[O:15])[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2.O>C(O)(=O)C>[C:17]1(=[O:18])[NH:1][C:14](=[O:15])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]1=2
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2=C1CCCC2

Procedure:
4.5 g (0.017 mole) of the above aniline and 2.7 g (0.018 mole) of cyclohexene-1,2-dicarboxylic anhydride in 70 ml of glacial acetic acid are stirred for 3 hours at 70° C. After the mixture has been cooled, 100 ml of water are added and the precipitate is filtered off, washed with water and dried. 3.5 g (52%) of N-[4-tetrahydropyran-4-ylmethyl)-3,3-dihydro-2H-1,4-benzoxazin -3-on-6-yl]-3,4,5,6-tetrahydrophthalimide (mp. 187-189° C.) are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>CN(C)C=O>[C:20](#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#CCCCCBr
Reactant: CCCCCOCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOCCCCCOCCCCC#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 0.75 g) was added to a solution of 3 g of 5-pentyloxy-l-pentanol prepared in the above-described step (1) in 50 ml of N,N-dimethylformamide. Then 2 ml of 5-bromopentanenitrile was added thereto and the mixture was stirred at 60° C. for 2 h. 3% hydrochloric acid was added to the reaction solution. After extraction with ether, the organic layer was dried and concentrated and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to obtain 1 g of the intended product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH:11]1[CH2:13][CH2:12]1
Reactant: Oc1ccccc1Br
Reactant: BrCC1CC1
Product: Brc1ccccc1OCC1CC1

Procedure:
Starting from commercially available 2-bromo-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:16]=[C:15]([F:25])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(#N)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:25])[CH:16]=[C:17]([C:19]4[CH2:20][N:21]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:22][CH2:23][CH:24]=4)[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cccnc4)c3)n2)nc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Fc1ccc(-c2noc(-c3cc(F)cc(C4=CCCN(Cc5ccccc5)C4)c3)n2)nc1
Temperature: 25 °C
Yield: 7.8 %

Procedure:
In a screw cap vial equipped with stir bar added 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (100 mg, 0.30 mmol), acetonitrile (2 ml) and benzyl bromide (0.05 ml, 0.39 mmol). Stirred the resulting mixture at 90° C. for 4h. Cooled the mixture to room temperature, concentrated in-vacuo and triturated the residue with 30% ethyl acetate in hexanes to isolate the quarternary salt. The isolated solid was dissolved in methanol (2 ml) and treated with sodium borohydride (22.6 mg, 0.60 mmol) at 0° C. The bright yellow reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in-vacuo and the residue was dissolved in dichloromethane (20 ml). The organic phase was sequentially washed with water (20 ml) and brine (20 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 30% ethyl acetate in hexanes to isolate the title compound (10.1 mg, 8%) as yellow oil. 1H-NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 8.02 (s, 1H), 7.80 (dd, 1H), 7.60 (dt, 1H), 7.32 (m, 6H), 6.34 (m, 1H), 3.73 (s, 2H), 3.40 (bs, 2H), 2.63 (t, 2H), 2.39 (m, 2H).