Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cccc(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
0.29 g of 3-fluoro-benzoic acid (2.03 mmol) and 0.7 g of 4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.03 mmol) were dissolved in 25 ml of dichloromethane. Addition of 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) at 0° C. was followed by stirring the reaction mixture for 16 h at room temperature. 30 ml of dichloromethane were added, the organic layer was washed with aqueous saturated sodium chloride. The aqueous phase was re-extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (15:1). Fractions containing the product were combined, the solvent was evaporated to yield 0.88 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[CH3:20][C:21]1[NH:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH3:20])[NH:22][CH:23]=3)=[O:27])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Yield: 10.4 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.0 g, 3.59 mmol) and 2-methyl-1H-imidazole-4-carboxylic acid (0.50 g, 3.95 mmol). The product purified twice by Flash-chromatography (normal phase and reverse phase). Yield 10.4%. 1H-NMR (400 MHz; DMSO): δ 1.07 (d, 3H), 2.30 (s, 3H), 4.22-4.50 (m, 3H), 7.02 (d, 2H), 7.42 (d, 1H), 7.86 (d, 1H), 7.93 (dd, 1H), 8.00 (d, HA), 8.07 (d, 1H), 12.11 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(C)C=CC=CC=1>[C:19]([C:13](=[CH:12][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: Cc1cccnc1N
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ncccc1C

Procedure:
A solution of 2-amino-3-methylpyridine (5.0 g., 0.0462 mole) and ethyl ethoxymethylenecyanoacetate (7.82 g., 0.0462 mole) in toluene (4 ml.) was heated for 15 minutes by means of an oil bath maintained at 100°. The solution was cooled and the title compound (9.1 g., 85%) collected by filtration. The product, m.p. 139°-143°, was recrystallized from 2-propanol to give an analytical sample, m.p. 144°-146°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH:15](O)[CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[O:17][CH:16]=[CH:15][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Solvent: CO
Product: c1ccc(CN2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After 3.055 g (8.403 mmol) of 1-benzyl-3-(2-tert-butyldimethylsiloxy-1-hydroxyethyl)-4-piperidinone was dissolved in 100 ml of methanol, 10 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature for 10 minutes. The solvent was distilled off under reduced pressure with heating. The resulting residue was dissolved in water. After this solution was alkalified with aqueous sodium hydroxide, it was extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 6/1) to yield 5-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:33][O:32][C:31]4=[O:41])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:33][O:32][C:31]4=[O:41])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OCC5c5ccccn5)nc34)cc2F)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCC(c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
To the solid 3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.36 g, 0.63 mmol) was added TFA (20 mL) and the reaction stirred at ambient temperature for 2 hours. The reaction was concentrated in vacuo and the material slurried in 1:1 methanol/acetonitrile (20 mL) with 10 mL of water, then stirred for 2 hours at ambient temperature. The reaction was concentrated in vacuo and the water layer basified to about pH 7 by the addition of saturated NaHCO3. The solids were filtered and washed with water. The solids were then slurried in 1:1 methanol/acetonitrile (20 mL) with 10 mL of water, and the organic solvents were removed in vacuo (3×). The residue was slurried in 1:1 methanol/acetonitrile (5 mL) with 10 mL of water and the solid filtered and washed with water to yield 3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.30 g, 0.68 mmol, 108% yield). LCMS (APCI+) m/z 443 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[CH:18])[CH:14]=[CH:13][C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].I[C:21]1[C:29]2[C:24](=NC=CC=2)[N:23]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:22]=1>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:33]([O:32][C:30]([N:23]1[C:24]2[CH:3]=[CH:4][CH:5]=[N:6][C:29]=2[C:21]([C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]([Cl:19])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[CH:16]=2)=[N:22]1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: C#Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cccnc21
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(C#Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ncccc21

Procedure:
A solution of 147 mg (0.51 mmol) of 3-chloro-5-(2-chloro-5-ethynylphenoxy)benzonitrile, 166 mg (0.48 mmol) of tert-butyl 3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate, 17 mg (0.03 mmol) of bis(triphenylphosphino)palladium (II) chloride, and 9.00 mg (0.05 mmol) of CuI in 2.5 mL DMF/5 mL triethylamine under nitrogen was stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo to a dark oil. The crude oil was purified by flash chromatography over silica gel with 2.5:1 hexanes/EtOAc to provide the desired product as a yellow oil/foam. M+=405 (M−100, loss of Boc). 1H NMR (CDCl3): 1.75 (s, 9H), 7.10 (m, 1H), 7.19 (m, 1H), 7.36 (m, 1H), 7.39 (m, 2H), 7.50 (dd, 1H), 7.56 (dd, 1H), 8.21 (dd, 1H), 8.82 (dd, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C(OCC)(=O)C>[N:41]([C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[N+:33]([O-:35])=[O:34])[CH2:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:13]3[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[NH:15][C:14]=3[CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:22]1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(N=[N+]=[N-])c5)CC4)cccc3[nH]2)cc1
Yield: 93 %

Procedure:
In a round bottom flask was combined 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (0.197 g, 0.40 mMol), dimethyl sulfoxide (3 mL), and sodium azide (0.029 g, 0.44 mMol) and the mixture stirred overnight. Upon arrival the mixture was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), washed with brine (50 mL), and the organics dried with magnesium sulfate and filtered. The organics were concentrated on a rotary evaporator to yield 190 mg (92% yield) of 4-[4-(3-Azido-4-nitro-benzyl)-piperazin-1-yl]-2-(4-tert-butyl-phenyl)-1H-benzoimidazole as a light yellow solid. 1H NMR (DMSO-d6): δ=12.69 (s, 1H), 8.04 (d, 2H, J=8.7 Hz), 8.01 (d, 1H, J=8.3 Hz), 7.57 (m, 1H), 7.54 (d, 2H, J=8.6 Hz), 7.39 (dd, 1H, J=8.5, 1.2 Hz), 7.03 (m, 2H), 6.50 (dd, 1H, J=5.5, 1.4 Hz), 3.70 (s, 2H), 3.60 (br s, 4H), 2.68 (br s, 4H), 1.33 (s, 9H). LC/MS (Method A), rt=1.41 mins., purity=89.8%, calculated mass=510, [M+H]+=511, [M−H]−=509.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.CN.CO.[CH2:34]([N:36](CC)CC)C.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[CH3:34][NH:36][C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:19][CH3:20])[N:9]=[CH:8][CH:7]=[C:6]2[O:5][C:4]1[CH:21]=[CH:22][C:23]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: CCN(CC)CC
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1Cl
Agent: CN
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NC)cc23)cc1Cl
Reaction time: 15 h
Yield: 74 %

Procedure:
After dissolving 4-(3-chloro-4-(((ethylamino)carbonyl) amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (104 mg, 0.250mmol) in dimethylformamide (3 ml), there were added a 40% methylamine-methanol solution (0.100 ml), triethylamine (0.250 ml) and 1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino)) phosphonium hexafluoro phosphate (221mg, 0.500mmol) in that order at room temperature, and the mixture was stirred for 15 hours. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out and blow-dried to obtain the title compound (79.0 mg, 0.184 mmol, 74%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12].CCN(C(C)C)C(C)C.[Br:26][CH2:27][C:28](Br)=[O:29]>C1COCC1>[Br:26][CH2:27][C:28]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])=[O:29]
Reactant: Nc1sc2c(c1C(=O)NCCO)CCCC2
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Reaction time: 0.5 h
Yield: 43 %

Procedure:
2-Amino-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (4.6 g, 19.14 mmol) and DIPEA (4.95 g, 6.33 mL, 38.3 mmol) were dissolved in THF (100 mL) and the mixture purged with nitrogen and cooled in an ice bath. 2-Bromoacetyl bromide (3.86 g, 1.667 mL, 19.14 mmol) dissolved in THF (5 mL) was added dropwise and the reaction monitored by TLC. After 30 min TLC indicated 3:1 product: starting material with a faint spot for bis-acylated material. An additional quantity of 2-bromoacetyl bromide (0.97 g, 0.417 μL, 4.79 mmol) was added and stirring continued for a further 30 min. The mixture was quenched by addition of water before removal of THF under reduced pressure. The mixture was then partitioned between EtOAc/water and the organic layer collected—additional DCM was added to aid solubility. The aqueous layer was further washed with DCM. Combined organics were dried and concentrated to give a thick dark oil which was purified on silica eluting with 20-60% EtOAc/heptane. Desired fractions were collected and concentrated to yield the desired product as a light yellow solid (2.96 g, 8.23 mmol, 43%). The sample was used directly in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:14][CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCN
Product: CCNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The mixture of 4-bromo-2-fluoro-1-nitrobenzene (5 g) and ethylamine (2 M in THF, 17.05 ml) was stirred at room temperature for 2 h and at 50° C. for 2 h. After concentration of the mixture, the residue was quenched with saturated NaHCO3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The progress of the reaction was followed by NMR, but 4-bromo-2-fluoro-1-nitrobenzene was remained. The resulting residue was dissolved in EtOH (25 ml), and heated with potassium carbonate (6.28 g) and ethylamine (15.6 M in water, 1.47 ml) at 50° C. for 2 h. The resulting suspension was filtered. The precipitate was washed with EtOH and water and dried to give the title compound (4.45 g) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C(C)=CC=CC=1.[Pd]>[OH:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[CH:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(O)C(=O)NCC1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc[nH]c(=O)c1O
Temperature: 130 °C
Yield: 75.8 %

Procedure:
To a solution of Intermediate 1A (20 g) in xylene (400 mL) was added 10% Pd/C (4 g). The mixture was heated at 130° C. for 24 h. The reaction was filtered through a pad of Celite®. Methanol was used for filtration and washing. The filtrate was concentrated and the residue was purified by ISCO flash chromatography (silica gel, 0-100% EtOAc/hexane) to give Intermediate 1B (15 g, 80% yield).
Reaction SMILES: [Cl-].[CH:2]1[C:7](N)=[CH:6][C:5]2[C:9]([O:11][C:12]3([C:22]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=4[O:20][C:14]4[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]3=4)[C:4]=2[CH:3]=1)=[O:10].CO.C1C=CC=CC=1>C1COCC1.N1C=CC=CC=1>[CH:2]1[CH:7]=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[C:4]([C:12]2[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[O:20][C:21]3[C:22]=2[CH:23]=[CH:24][C:25]([CH:26]=3)=[O:27])[CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 0 °C

Procedure:
A solution of myristoryl chloride (2.18 g, 8.83 mmol) in THF was added to a solution of fluoresceinamine-isomer 1 from Aldrich Chemical Co. (3.07 g, 8.85 mmol) in dry pyridine (dried over basic alumina) dropwise with stirring at room temperature over a 12 hour period. TLC on silica with 20% MeOH/benzene showed conversion to a less polar product. The reaction was poured into ice water and the solid precipitate isolated by filtration to give 4 g of solid orange material Column chromatography with 10% MeOH/benzene afforded 500 mg of the pure product as an orange solid: mp 185-190° C.; 1H NMR (CDCl3)δ 0.88 (t, 3H), 1.27 (m, 20H), 1.74 (m, 2H), 2.42 (t, 2H), 6.54-8.32 (m, 9H); 13C NMR (CDCl3) δ 13.05, 22.27, 25.34, 28.90, 29.01, 29.17, 29.31, 31.61, 36.65, 101.00, 110.25, 112.43, 114.93, 124.41, 126.58, 127.86, 128.77, 140.41, 147.00, 152.89, 160.28, 169.96, 173.65; MS (FAB) m/e (rel intensity) 558 (10, M+1), 402 (14.7), 388 (14.2), 374 (12.5), 348 (28.1), 302 (35.2), 213 (36.4), 165 (36.4), 133 (50). The properties of 3 are in agreement with those described for the commercially available material from Molecular Probes, Inc. ##STR28##
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].[OH-].[Na+]>CO>[CH3:30][N:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH2:15][CH2:16]1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccccc4)CC3)cc2o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-[trans-4-(3-phenylpropylamino)cyclohexyl]-3H-benzoxazol-2-one (263 mg, 0.750 mmol) in MeOH (10 mL) was added H2O (0.5 mL) and p-formaldehyde (113 mg, 3.75 mmol). After stirring the reaction mixture for 3 hours, NaBH(OAc)3 was added, and stirring was continued for 12 hours. Solid NaOH was added to give a clear solution, which was then concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[methyl(3-phenylpropyl)-amino]cyclohexyl}-3H-benzoxazol-2-one (160 mg, 59%), as a white solid: mp 58-62° C.; IR (KBr): 2929, 1774 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 8.97 (br s, 1H), 7.26-7.12 (m, 6H), 6.99-6.98 (m, 2H), 2.63 (m, 2H), 2.57 (t, J=7 Hz, 2H), 2.56 (m, 1H), 2.38 (m, 2H), 2.18 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.27 (m, 2H); CI-MS (methane) (m/z): 365 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C23H28N2O2, 365.2229; found, 365.2231; HPLC: method A, 5.95 minutes (95.3%); method B, 10.12 minutes (97.6%); Anal. Calcd for C23H28N2O2.0.25H2O: C, 74.87; H, 7.79; N, 7.59. Found: C, 74.77; H, 7.71; N, 7.81.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH3:11][C:12]([S@:15](/[N:17]=[CH:18]/[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:16])([CH3:14])[CH3:13]>C1COCC1.BrCCBr>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@H:18]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[NH:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[CH:3][C:4]=1[F:9]
Reactant: Fc1cc(Br)ccc1Cl
Reactant: Cn1cc(/C=N/[S@](=O)C(C)(C)C)cn1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cn1cc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(Cl)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a mixture of 4-bromo-1-chloro-2-fluorobenzene (11.7 g, 56.0 mmol) and magnesium turnings (2.1 g, 84 mmol) in THF (150 mL) at RT was added a few drops of 1,2-dibromoethane (1.1 g, 5.6 mmol). The mixture was stirred at RT for 1.5 h. After cooling to −78° C., (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (4.00 g, 18.7 mmol) was added and stirred at −78° C. for 6 h. The reaction was quenched with aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (150:1) to afford the 2.9 g (45%) of (R)—N—((S)-(4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (48). LCMS (ESI) m/z: 344.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:25]([CH3:26])=[CH:24][C:6]2[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:26][C:25]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1
Reactant: Cc1cc2c(cc1C#N)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C#N)[nH]c(=O)n2C1CCNCC1
Reaction time: 1 h
Yield: 102.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-(5-cyano-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D93) (2.6 mmol, 1.15 g crude material) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) under argon at room temperature and was allowed to stir for 1 h. The mixture was then concentrated under reduced pressure, the residue was treated with 10% aqueous sodium carbonate solution and extracted 3 times with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure to give the title compound (2.66 mmol, 680 mg, ˜100%). M+H 257.2.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O.[NH2:13]N.O>C(O)C>[NH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: NN
Reactant: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CCO
Product: NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42 %

Procedure:
Phthalimide powder was added to a solution of hydrazine monohydrate (28.9 mL, 462.4 mmol) in ethanol (415 mL). The resulting solution was stirred at room temperature for 2 minutes and then stirred under reflux for 8 minutes. The resulting mixture was added to icy water to precipitate solid. The resulting solid was filtered, collected, washed with a small volume of water, and then dried in vacuum. The target compound was yielded as white solid (29.5 g, 182.1 mmol, 42% yield).