Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:36]([CH2:38][NH2:39])[OH:37]>CN(C=O)C.C(OCC)(=O)C>[OH:37][CH2:36][CH2:38][NH:39][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: NCCO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of quinaldic acid (5.0 g, 28.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g, 28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60 mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and 4-methylmorpholihne (4.76 mL, 43.31 mmol). The reaction was stirred at 0° C. for an additional 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed 3 times with H2O, once with NaHCO3 (sat), once with brine, dried over MgSO4, and concentrated in vacuo to provide 1.5 g (24% yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)+.
Reaction SMILES: [N+:1](=[CH:3][Si](C)(C)C)=[N-:2].[CH2:8]1[C@@H:13]2[CH2:14][C:15]3([C:17](Cl)=[O:18])[CH2:16][C@H:9]1[CH2:10][CH:11]3[CH2:12]2>CCOCC.C(#N)C.C1COCC1.CCOC(C)=O>[CH2:8]1[CH:9]2[CH2:16][C:15]3([C:17]([O-:18])=[CH:3][N+:1]#[N:2])[CH2:14][CH:13]1[CH2:12][CH:11]3[CH2:10]2
Reactant: O=C(Cl)C12C[C@@H]3CC1C[C@@H](C3)C2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#[N+]C=C([O-])C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
A solution of (diazomethyl)trimethylsilane (2.70 mL, 5.40 mmol) in Et2O was added to a solution of 3-noradamantanecarbonyl chloride (0.495 g, 2.68 mmol) in acetonitrile (4 mL) and THF (4 mL), stirred at room temperature overnight, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 551 mg of crude title compound as a yellow solid: MS (APCI+) M/Z 191 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.O[CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([C:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH:23]=3)=[C:17]([F:35])[CH:16]=2)[CH2:10]1>>[O:1]=[C:2]1[CH:6]=[CH:5][O:4][N:3]1[CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]([F:35])[C:18]([C:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH:23]=3)=[C:19]([F:21])[CH:20]=2)[CH2:10]1
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: Oc1ccon1
Product: O=C1O[C@@H](Cn2occc2=O)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
During the Mitsunobu reaction the ambident nucleophile 3-hydroxyisoxazole reacts with 5(R)-Hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one to give a quantity of 5(R)-(3-Oxo-isoxazol-2-ylmethyl)-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one. Failure to purify (e.g. by suitable column chromatography) the product from the Mitsunobu reaction described in GB99/01753 before subsequent reaction with 1-chloroethyl chloroformate and work-up using hydrochloric acid gives a quantity of 5(R)-(3-Oxo-isoxazol-2-ylmethyl)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one as the hydrochloride salt, which is identified in the mixture by correlation TOCSY NMR (TOtal Correlation SpectroscopY)— methylene carbon attached to the nitrogen of the isoxazolone ring has a shift of 48 ppm (characteristic of this linkage), and by LC-MS (MH+ 378-less chloride) using C-18 Hichrom RPB column, 5 mm, 25 cm×0.46 mm i.d; Eluant—650 ml Water, 350 ml Acetonitrile, 1 ml TFA (biograde); Flow—1.5 ml/min; Retention Times N-linked-Piperidene—Rt=2.0 min, O-linked Piperidene—Rt=3.25 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH2:10])=[N:2]1.[OH-].[K+].Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[H-].[Na+]>CS(C)=O.O>[CH3:21][C:18]1[S:19][CH:20]=[C:16]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([NH2:10])=[N:2]2)[N:17]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Nc1n[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(Cn2nc(N)c3ccccc32)cs1
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
A solution of 1H-indazol-3-amine (ABCR, 700 mg, 5.26 mmol) in anhydrous DMSO (10 ml) was added to a suspension of potassium hydroxide (PANREAC, 737 mg, 13.14 mmol) in anhydrous DMSO (40 mL) and this mixture was stirred for 10 min. A solution of 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (BUTTPARK, 776 mg, 5.26 mmol) and sodium hydride (ALDRICH, 126 mg, 5.26 mmol) in anhydrous DMSO (10 mL) was added dropwise to the mixture. Reaction was stirred at room temperature for 32 hours. Mixture of reaction was poured into water (100 mL) and extracted using DCM (4×100 mL). The combined organics were washed with water:brine (1:1) (100 mL) and dried over MgSO4 (anh), filtered and concentrated to dryness. Residue was purified using silica chromatography column using a linear gradient of DCM/MeOH (0%--->5%) as eluents to give the title compound 1-[(2-methyl-1,3-thiazol-4-yl)methyl]-1H-indazol-3-amine (988 mg, 4.04 mmol, 77% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.67-7.69 (m, 1H), 7.40-7.43 (m, 1H), 7.23-7.28 (m, 1H), 7.07 (s, 1H), 6.90-6.90 (m, 1H), 5.46 (br s, 2H), 5.31 (s, 2H), 2.57 (s, 3H). [ES+MS] m/z 245 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:16]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (Boc-Phe(4-I)-OH) (15.0 g, 38.3 mmol) was dissolved in DMF (180.0 ml), and piperidine (7.95 ml, 80.6 mmol), HATU (17.5 g, 46.0 mmol) and DIPEA (8.01 ml, 46.0 mmol) were added under ice-cooling. After stirring at room temperature for 30 minutes, the reaction solution was diluted with hexane/ethyl acetate (1/1, 400 ml) and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered and concentrated under reduced pressure to afford the title compound SP413 (16.9 g, 96%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32])=[CH:24][CH:23]=2)[C:7]1=[O:34].O.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]([CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:27]=3)[C:7](=[O:34])[N:6]([CH2:5][C:4]3[CH:35]=[CH:36][CH:37]=[C:2]([Cl:1])[CH:3]=3)[C:11]=2[CH:12]=1
Reactant: N=C(N)NCCc1ccc(OCCC2Oc3ccc([N+](=O)[O-])cc3N(Cc3cccc(Cl)c3)C2=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N=C(N)NCCc1ccc(OCCC2Oc3ccc(N)cc3N(Cc3cccc(Cl)c3)C2=O)cc1
Yield: 85 %

Procedure:
4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-[4-(2-guanidinoethyl)phenoxy]ethyl}-6-nitro-3-oxo-2H-1,4-benzoxazine (0.3 g) was warmed in ethanol (5 ml) and H2O (4 ml) until completely in solution. Iron powder (0.19 g, 6.8 eq) was stirred in followed by NH4Cl (0.02 g, 0.7 eq) and the reaction continued at reflux for 5 hours. While still hot, the mixture was filtered through celite and the yellow filtrate concentrated down to a yellow oil. After drying in vacuo at 80 C.°, the product was collected as a yellow solid in 85% yield, mp (dec)>94° C.; MS (Cl) MH+ 494; IR (KBr) 3332, 1667, 1614, 1512, 1467, 1396, 1243, 830, 774, 680 cm-1 ; 1H NMR (DMSO-d6 /CDCl3) δ 7.66 (br s, 1H), 7.58-6.50 (v br s, 3H), 7.36 (m, 4H), 7.20 (m, 3H), 6.91 (d, 2H, J=8.6 Hz), 6.74 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=2.2 Hz), 6.21 (dd, 1H, J=2.2, 8.4 Hz), 5.08 (d, 1H, J=16.7 Hz), 4.99 (d, 1H, J=16.5 Hz), 5.12-4.78(v br s., 1H), 4.79 (dd, 1H, J=4.0, 8.9 Hz), 4.15 (m, 2H), 3.33 (m, 2H), 2.71 (t, 2H, J=7.5 Hz), 2.30 (m, 1H), 2.18 (m, 1H). Anal. Calc'd for C26H28ClN5O3.HCl.0.5 H2O: C 57.89, H 5.61, N 12.98. Found: C 57.64, H 5.48, N 12.63.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@@H:23]([CH:32]=[CH2:33])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([CH2:27][CH2:28][C:29]([O:31][CH3:1])=[O:30])[C@@H:23]([CH:32]=[CH2:33])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)OC
Temperature: 22 °C
Reaction time: 3 h

Procedure:
50 cm3 of a solution of 2M trimethylsilyldiazomethane/hexane are added, at a temperature in the region of 15° C., under an argon atmosphere, to 5 g (17.64 mmol) of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-carboxyethyl)-3-vinylpiperidine in solution in 50 cm3 of methanol. After stirring for 3 hours at a temperature in the region of 22° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give 5.3 g of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-methoxycarbonylethyl)-3-vinylpiperidine in the form of an orange oil.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:2]2[C:10]3[O:9][C:8]([F:12])([F:11])[O:7][C:6]=3[C:5]([F:13])=[CH:4][CH:3]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)c2c1OC(F)(F)O2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(F)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -5 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
4-Bromo-2,2,7-trifluorobenzo[d][1,3]dioxole (2.0 g, 7.8 mmol) was dissolved in dry tetrahydrofuran (12 ml), cooled to −5° C. and treated in portions with isopropylmagnesium lithium chloride complex (1.3 M; 6.3 mL, 8.2 mmol). The mixture was stirred for 2 h at 5 to 15° C., treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.4 mmol) and stirred for 2 h at 10 to 20° C. The mixture was treated with saturated NH4Cl (5 mL), stirred for 10 min and then shaken with 1 M HCl (10 mL) and ethyl acetate (75 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (2.3 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J=8.7, 5.3 Hz, 1H), 6.88 (dd, J=9.5, 8.8 Hz, 1H), 1.36 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.07, −131.31; EIMS m/z 302.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:16])=[C:12]([CH2:14]Cl)[N:13]=2)=[CH:5][CH:4]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C.O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=4)[NH:10][C:11]=3[CH3:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(-c2nc(CCl)c(C)[nH]2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c(C)[nH]2)cc1

Procedure:
50 Grams (0.2 mol) of 2-(4-methylphenyl)-4-chloromethyl-5-methyl-1H-imidazole hydrochloride dissolved in 200 ml of a mixture of ethanol:water 6:4 were added dropwise to a refluxing solution of 55 grams (0.2 mol) of N-(diphenylmethyl)piperazine and 24 grams (0.6 mol) sodium hydroxide in 200 ml of a mixture of ethanol:water 6:4. After 2 to 3 hours 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4yl)methyl]piperazine precipitated from the reaction mixture. After having left the crystals standing at room temperature, they were removed by filtration and recrystallized from methanol to give the free base which melted at 220°-222° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[N:6][C:5]([N+:11]([O-])=O)=[C:4]([NH2:14])[N:3]=1.[H][H]>[Pd].O>[NH2:1][C:2]1[C:7]([NH2:8])=[N:6][C:5]([NH2:11])=[C:4]([NH2:14])[N:3]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])nc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Nc1nc(N)c(N)nc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,6-Diamino 3,5-dinitro pyrazine (150 g, 75 mmol), 5% palladium on carbon (2.0 g) and deoxygenated water (200 mL) was added to a parr shaker and charged with 50 psi of hydrogen and allowed to shake at room temperature tor 24 hours. The reaction mixture was added to deoxygenated boiling water (750 mL) and filtered hot. The filtrate was allowed to cool to room temperature and the resulting solid was recrystallized from concentrated HCl (16.1 g, 80.1%). Crystal exists as a trihydrogen chloride mono hydrate system.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[CH:27]2.C(N(CC)CC)C.O.O.C(O)(=O)C(O)=O>CS(C)=O.ClCCl.C(O)C>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[CH2:12][N:37]1[CH2:38][CH2:39][CH:34]([CH2:33][C:28]2[NH:29][C:30]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:23])=[CH:32][CH:31]=3)[CH2:35][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Reactant: Fc1ccc2[nH]c(CC3CCNCC3)cc2c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CS(C)=O
Solvent: ClCCl
Product: Fc1ccc2[nH]c(CC3CCN(CC4CCc5ccccc5O4)CC3)cc2c1
Temperature: 90 °C
Yield: 44.6 %

Procedure:
To a solution of 3,4-dihydro-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate (0.70 g, 2.19 mmol) in methyl sulfoxide (20 mL) was added 5-fluoro-2-(4-piperidinylmethyl)-1H-indole (0.51 g, 2.19 mmol) and triethylamine (0.25 g, 2.30 mmol) and the reaction mixture was heated to 90° C. for 8 h. The reaction mixture was allowed to cool to room temperature and was diluted with dichloromethane (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:dichloromethane 1:19) provided a colorless oil which was dissolved in ethyl alcohol (5 mL) and treated with a solution of oxalic acid dihydrate (0.244 g, 1.94 mmol) in ethyl alcohol (10 mL). The resulting solid was filtered, washed (hexanes), and dried to give 0.370 g (44%) of 2-{[1-(3,4-dihydro-2H-chromen-2-ylmethyl)-4-piperidinyl]methyl}-5-fluoro-1H-indole as a white solid. mp 187-190° C.; Anal. Calcd. for C24H27FN2O.0.5 C2O4H2.0.5H2O: C, 69.43; H, 6.76; N, 6.48. Found: C, 69.23; H, 6.83; N, 6.48.
Reaction SMILES: C(OC(=O)C[CH2:12][C:13]1[CH:18]=[C:17]([N:19]2[N:23]=[C:22]3[CH:24]=[CH:25][CH:26]=[C:27](Cl)[C:21]3=[N:20]2)[C:16]([OH:29])=[C:15]([C:30](C)(C)C)[CH:14]=1)CCCCCCC.[CH2:35](C(CCCC)COC(=O)CCC1C=C(N2N=C3C=CC(Cl)=CC3=N2)C(O)=C(C(C)(C)C)C=1)[CH3:36]>>[CH3:12][C:13]1[CH:18]=[C:17]([N:19]2[N:23]=[C:22]3[C:21]([CH:27]=[CH:26][CH:25]=[CH:24]3)=[N:20]2)[C:16]([OH:29])=[C:15]([CH2:30][CH:35]=[CH2:36])[CH:14]=1
Reactant: CCCCC(CC)COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCOC(=O)CCc1cc(-n2nc3cccc(Cl)c3n2)c(O)c(C(C)(C)C)c1
Product: C=CCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Mixture of octyl-3-[3-tert-butyl-4-hydroxy-5-(chloro-2H-benzotriazole-2-yl)phenyl]propionate and 2-ethylhexyl-3-[3-tert-butyl-4-hydroxy-5-(5-chloro-2H-benzotriazole-2-yl)phenyl]propionate (TINUVIN109, Ciba Specialty Chemicals Inc.)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CO>C(Cl)Cl>[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([CH:27]3[O:28][CH2:29][CH2:30][NH:25][CH2:26]3)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1)C1CNCCO1
Reaction time: 1 h

Procedure:
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole hydrochloride (140 mg) is added at room temperature to a solution which has been prepared by adding morpholine (298 mg, a 30% methanol solution) to methylene chloride (10 ml) . After the reaction mixture is stirred for one hour at the same temperature, it is washed with water, dried and concentrated under reduced pressure. The residue is recrystallized using ether and thus, 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholino-carbonylbenzimidazole (20 mg) is obtained. (Colorless crystal). 1H-NMR (CDCl3,): 1.04-1.12 (2H, m), 1.25-1.32 (2H, m), 1.82-1.96 (1H, m), 3.68 (8H, bs), 5.56 (2H, s), 6.55 (1H, dd, J=1, 8 Hz), 7.13 (1H, dt, J=1, 8 Hz), 7.22-7.29 (2H, m), 7.30 (1H, d, J=1 Hz), 7.46 (1H, dd, J=1, 8 Hz), 7.77 (1H, d, J=8 Hz).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([O-:13])=O)[CH3:7].[Br:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:19](C(Cl)=O)=[C:18]([F:27])[C:17]=1[F:28].Cl>O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1>[Br:15][C:16]1[C:17]([F:28])=[C:18]([F:27])[C:19]([C:11]([CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:14])=[O:13])=[C:23]([F:26])[C:24]=1[F:25]
Reactant: O=C(Cl)c1c(F)c(F)c(Br)c(F)c1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
n-Butyllithium (192 ml, 2.4M in hexane) was slowly added to a stirred solution of 30.24 g monoethylmalonate and 15 mg 2,2'-bipyridine in 500 ml tetrahydrofuran cooled to -60° to -70° C. under nitrogen. After about half of the butyllithium had been added, the temperature of the mixture was raised to -20° to -25° C. at which temperature the remainder of the butyllithium was added. The reaction mixture was then recooled to -60° to -70° C. and 33.41 g 4-bromo-2,3,5,6-tetrafluorobenzoyl chloride in 10 ml tetrahydrofuran was added. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then poured into 460 ml 1M hydrochloric acid. The organic layer was separated, dried (magnesium sulfate) and concentrated. The residue was dissolved in ether, washed with aqueous potassium bicarbonate solution, dried (magnesium sulfate), concentrated and distilled to give 34.18 g ethyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate, b.p. 112° -117° C. (0.8 mm).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47]C3CCCCO3)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOC3CCCCO3)c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCO)c2)n1
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To a solution of Intermediate 108c (170 mg, 0.23 mmol) in MeOH (2.5 mL) was added pyridinium p-toluenesulfonate (118 mg, 0.47 mmol) and the reaction mixture was heated at 60° C. for 2 h. The resultant mixture was poured into water and a saturated aqueous solution of NaHCO3 was added. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to give the title compound (105 mg, 72%). LCMS (Method 1): Rt 2.96 min, m/z 639 [MH+].
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([C@@H:24]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:25]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:22][O:21][C:20](=[O:58])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH:23]([C@@H:24]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:25]([N:35]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:22][O:21][C@@H:20]([OH:58])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)OCC1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add diisobutylaluminum hydride (1.4 mL, 1.37 mmol, 1.0 M in toluene) to a solution of (R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-oxomorpholine-4-carboxylic acid tert-butyl ester (0.75 g, 1.1 mmol) in of dry toluene (15 mL) at −78° C. under nitrogen and stir at this temperature for 2 hours (Monitor by TLC). Add methanol to quench the reaction (1.0 mL), then saturated aqueous potassium sodium tartrate (Rochelle salt) and ethyl acetate. Warm to room temperature and stir vigorously for 30 minutes. Separate the organic layer and extract the aqueous with ethyl acetate. Combine the organic layers and dry (magnesium sulfate), filter and concentrate to give the desired compound as a mixture of the two possible isomers as a white solid and used in the next step without further purification (0.75 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[O:11]=[C:9]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]1)[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2cccnc2)CC1

Procedure:
A sample of 3-pyridinepropanoic acid (0.1 g, 0.7 mmol) was reacted with t-butyloxycarbonyl piperazine (0.19 g, 1.0 mmol) by the method of Example 26 to produce 95 mg of the white solid title compound after chromatography.