Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([NH:9][C:10]1[C:14]([C:15](OCC)=[O:16])=[CH:13][N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=1)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][NH:9][C:10]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1NC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nn(-c2ccccc2)cc1CO
Reaction time: 2 h
Yield: 96 %

Procedure:
Lithium aluminum hydride (7.50 g) was added to tetrahydrofuran (200 mL) under ice-cooling. To the obtained mixture was added dropwise a solution (100 mL) of ethyl 3-(formylamino)-1-phenyl-1H-pyrazole-4-carboxylate (20.50 g) in tetrahydrofuran, and the mixture was heated under reflux for 1.5 hrs. To the obtained mixture was added small portions of sodium sulfate decahydrate (50 g) on an ice bath, and the mixture was stirred for 2 hrs. while adding tetrahydrofuran (50 mL) as appropriate to allow stirring. Solids were filtered off and the filtrate was concentrated to give [3-(methylamino)-1-phenyl-1H-pyrazol-4-yl]methanol as a colorless oil (15.42 g, yield 96%).
Reaction SMILES: [CH3:1][NH2:2].CS([C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[C:9]([CH2:16][CH2:17][CH3:18])[N:8]=1)(=O)=O>>[CH3:1][NH:2][C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[C:9]([CH2:16][CH2:17][CH3:18])[N:8]=1
Reactant: CCCc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Reactant: CN
Product: CCCc1cc(C(=O)O)nc(NC)n1

Procedure:
A solution of 40% aq. methylamine (5 mL) and 2-methanesulfonyl-6-propyl-pyrimidine-4-carboxylic acid (150 mg, 0.614 mmol) is heated to 70° C. for 2 h. The reaction mixture is then evaporated and the crude compound is dissolved in 3N NaOH solution (10 mL). The aq. solution is washed with EtOAc (5 mL), is then adjusted to pH 3 with 25% aq. HCl and finally extracted with DCM (3×15 mL). The combined DCM extracts are dried over MgSO4, filtered and evaporated to give 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid as a beige powder (128 mg); LC-MS: tR=0.56 min, [M+H]+=196.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C.C(O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CN(c3ncccn3)CC2C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.0 g, 4.7 mmol), 2-chloropyrimidine (0.54 g, 4.7 mmol), triethylamine (2 ml, 14 mmol) and ethyl alcohol (25 ml) was maintained at reflux for 4 hours. The solution was then cooled to room temperature and concentrated to afford a solid residue that was dissolved in dichloromethane (CH2Cl2), which was washed sequentially with sat. aq. sodium bicarbonate and brine, dried (Na2SO4), filtered, and concentrated to afford 0.82 g (60%) of the product as an orange solid: 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 3.86-3.79 (m, 2H), 3.72-3.62 (m, 2H), 3.57-3.50 (m, 2H), 3.41-3.33 (m, 1H), 3.33-3.26 (m, 1H), 3.05-2.96 (m, 2H), 1.47 (s, 9H); LRMS m/z 291 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.[CH3:21][O:22][P:23](Cl)(=[O:26])[O:24][CH3:25]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[O:15]=[C:12]1[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:13]1[P:23](=[O:26])([O:24][CH3:25])[O:22][CH3:21]
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Reactant: COP(=O)(Cl)OC
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COP(=O)(OC)N1C[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.13 h

Procedure:
3-[(Phenylacetyl)amino]-2-azetidinone (250 mg)was dissolved in a mixture of dry dimethylformamide (2 ml) and anhydrous tetrahydrofuran (5 ml). The mixture was cooled to -78° C., sec-butyllithium (0.83 ml of 1.4 N in cyclohexane) was added, stirring was continued for 8 minutes dimethylphosphorochloridate (187 μl) was added, and the mixture was stirred for 45 minutes at -78° C. After dilution with saturated aqueous sodium chloride and two extractions with ethyl acetate, the combined extracts were dried (sodium sulfate), filtered, and solvent was removed in vacuo yielding an oil. Thin-layer chromatography on plates developed in ethyl acetate gave the product as an oil which crystallized from ether. The solid was recrystallized from ethyl acetateether-pentane, triturated with ether, and dried in vacuo yielding 283 mg of the title compound as a powder, melting point 77.5°-81.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]([CH3:59])[C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:52](=[O:53])[C@H:51]([C:55]([CH3:57])([CH3:56])[CH3:58])[NH:50][C:48](=[O:49])[N:47]([CH3:59])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN(Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.4 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 63C (0.013 g, 0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 45 minutes. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.017 g, 57% yield). 1H NMR (300 MHz, DMSO-d) δ ppm 0.80(s, 9H), 0.81(s, 9H), 1.58-1.49(m, 2H), 2.74-2.72(m, 3H), 2.79(s, 3H), 3.49(s, 3H), 3.67-3.61(m, 1H), 3.84-3.81(d, J=9.93 Hz, 1H), 4.12-3.99(m, 1H), 4.16-4.13(d, J=8.82 Hz, 2H), 4.44(s, 2H), 4.82-4.80(d, J=5.88 Hz, 1H), 5.40-5.37(d, J=9.19 Hz, 1H), 6.62-6.59(d, J=9.93 Hz, 1H), 7.35-7.10(m, 13H), 7.67-7.64(d, J=8.82 Hz, 1H), 7.82-7.77(m, 1H), 7.88-7.84(m, 4H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[C:26]([C:28]1[CH:29]=[CH:30][C:31](F)=[N:32][C:33]=1[CH3:34])#[N:27].N12CCN(CC1)CC2>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[C:33]([CH3:34])[N:32]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: Cc1nc(F)ccc1C#N
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: Cc1nc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1C#N

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 5-cyano-2-fluoro-6-picoline in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=492.1 [M+H+].
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13]>CCO>[OH:13][N:12]=[C:10]([NH2:11])[CH2:9][CH2:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCNc1ccccc1
Reactant: NO
Solvent: CCO
Product: NC(CCNc1ccccc1)=NO
Yield: 62.8 %

Procedure:
A solution of 3-(phenylamino)propanenitrile (1 g, 6.84 mmol) and NH2OH (50% in water, 0.63 cm3, 10.26 mmol) in EtOH (10 cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. To the residue was added water (10 cm3) and the mixture was extracted with CH2Cl2 (100 cm3). The extracts were concentrated under reduced pressure and the residue was purified by column chromatography (silica, Et2O) to give N′-hydroxy-3-(phenylamino)propanimidamide (0.77 g, 62.8%) as a white solid, mp 93-95° C. (lit mp 91-91.5° C.).
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[C:23]([F:26])([F:25])[F:24])[O:16][CH2:15]1>>[F:25][C:23]([F:24])([F:26])[C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]=12
Reactant: CON=C1COc2nccc(C(F)(F)F)c21
Agent: NC1COc2nnccc21
Product: NC1COc2nccc(C(F)(F)F)c21

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-(trifluoromethyl)furo[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.O.[OH-].[Na+]>[Cl-].[Na+].O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[CH3:11]
Reactant: BrCCCBr
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCCBr
Yield: 55.4 %

Procedure:
2,6-Dimethyl-4-nitrophenol (5.2 g) and 12.6 g of 1,3-dibromopropane were added to 19 mL of distilled water, the mixture was stirred, and 7.51 g of a 16.6% aqueous sodium hydroxide solution was then added thereto. Further, the mixture was heated under reflux while adding 2.46 g of a 30% aqueous sodium hydroxide solution for 5 hr. The reaction mixture was cooled, and ethyl acetate and brine were added thereto, followed by separation and washing with brine. The ethyl acetate layer was concentrated under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 4.97 g of 2-(3-bromopropoxy)-1,3-dimethyl-5-nitrobenzene. Next, 1.0 g of the product, 0.57 g of 4-trifluoromethylphenol, 2 mL of dimethylacetamide, and 0.36 g of potassium carbonate were mixed together, and the mixture was heated at 90 to 100° C. for one hr. The reaction solution was cooled and was then poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% aqueous sodium hydroxide solution and brine and was then concentrated under the reduced pressure to give 1.28 g of 1,3-dimethyl-5-nitro-2-(3-(4-trifluoromethylphenoxy)propoxy)benzene.
Reaction SMILES: ClC1C=CC(C([NH:10][C:11]2[O:12][C@H:13]([C:35]([F:38])([F:37])[F:36])[CH2:14][C@:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)[CH:21]=[CH:20][C:19]=3[F:34])([CH3:17])[N:16]=2)=O)=NC=1>N.CO>[NH2:10][C:11]1[O:12][C@H:13]([C:35]([F:36])([F:38])[F:37])[CH2:14][C@:15]([C:18]2[CH:23]=[C:22]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=3)[CH:21]=[CH:20][C:19]=2[F:34])([CH3:17])[N:16]=1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc(Cl)cn2)=N1
Agent: N
Solvent: CO
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Yield: 74.7 %

Procedure:
A solution of 5-chloro-N-((4S,6S)-4-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)picolinamide (4k 85.3 mg, 0.150 mmol) in 2 M NH3/MeOH (Aldrich; 4.0 mL) was heated to 50° C. for 16 h. The solution was concentrated and purified by flash chromatography on silica gel (Gradient: 20%→100% EtOAc/hexane) to give the title compound (48.2 mg, 0.112 mmol) as a white solid. MS m/z=431.0, [M+H]+. Calculated for C18H15ClF4N4O2: 430.8
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[N:16]#N.N>CCCCCC.CN(C=O)C.CCOCC.O>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([NH2:16])=[O:4]
Reactant: N#N
Reactant: C=CCC(F)(F)C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCC(F)(F)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of 2,2-difluoropent-4-enoic acid (27.2 g, 0.2 mol) in hexane (200 mi) in a three-neck flask equipped with a reflux condenser and M2 inlet is added DMF (20 drops, catalytic) and oxalyl chloride (20 mL, 0.23 mol). The mixture is stirred at room temperature for 2 h, when no further evolution of gas is seen. The solution is cooled in an ice/brine bath, the N2 inlet is replaced by an empty CaCl2 tube (to trap any solid material blown out of the flask), and a stream of NH3 gas is passed into the flask. The gas flow is maintained for 30 min after the initial vigorous reaction has subsided. The mixture is then poured into H2O (1 L) and Et2O (0.5 L). The glassware is washed with H2O and Et2O, and the washings are added to this mixture. Celite is added and insoluble material is removed by filtration. The phases are separated. The Et2O phase is washed once with brine, dried over Na2SO4, and concentrated. The aqueous phase is extracted twice with CH2Cl2. The combined extracts are washed once with brine, dried over Na2SO4, combined with the residue of the ethereal phase, and concentrated. The residue is distilled to give the title amide (20.6 g, 76%) bp 100°-110° C/10 Torr, as a slightly yellow oil which solidifies on cooling, mp 33°-35° C. 1H NMR (CDCl3)δ7.0-6.0 (2H, br.d), 5.75 (1 H, ddt, J=18, 9, 6 Hz), 5.3 (2 H, m), 2.87 (2 H, dt, J=6, 17 Hz). 19F NMR (δC6F6 =O) δ-56.0 (t, J=17 Hz).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:10]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:11][C:12]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3C(=O)[C:18]3[C:13]=2[C:14]=1[CH:15]=[CH:16][CH:17]=3.CN([CH:39]=[O:40])C.Cl.N([O-])=O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:28]([O:27][C:10]1[CH:11]=[C:12]2[C:25]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:39](=[O:40])[C:18]3[CH:17]=[CH:16][C:15]4[C:4]5[C:3]([S:8][C:9]=1[C:14]=4[C:13]2=3)=[CH:2][CH:7]=[CH:6][CH:5]=5)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCOc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Reactant: CN(C)C=O
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CCCCCCCCOc1cc2c3ccccc3c(=O)c3ccc4c5ccccc5sc1c4c32
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Into a 2 liter three-necked round bottom flask, equipped with a mechanical stirrer and a thermometer, containing 77 g 3-[(2-aminophenyl)thio]-2-n-octyloxy-7H-benzo[de]anthracene-7-one (0.16M), placed into an ice bath, was added 1100 ml of DMF. The mixture was cooled to 10° C. while stirring. 35% Hydrochloric acid (247 ml) was added portionwise, ensuring that the reaction temperature did not exceed 20° C. After the HCl addition was complete, the reaction was cooled to 0° C. and a solution of 14.0 g (0.2M) NaNO2 in 78 ml of H2O was added portionwise, making sure that the reaction temperature did not rise above 5° C. The reaction mixture was held at 5° C. for an additional 1 hour after the completion of the sodium nitrite addition. Then, during the addition of 5.2 g copper sulfate catalyst, the reaction was heated, and at 15° C., nitrogen bubbles began to evolve. The reaction mass was held at 100° C. for 1.5 hours, cooled and the red colored precipitate was filtered and washed with water, then ethanol. The yield=66.89 g (90%); Tm=205-208° C.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C:12](=[O:13])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH2:36]([NH:37][C:12]([C@@H:14]([C@H:15]([C@@H:9]([C@@H:10]([CH2:18][OH:19])[OH:11])[O:8][C@@H:6]1[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]1[OH:20])[OH:16])[OH:17])=[O:13])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:12]([C@@H:14]([C@H:15]([C@@H:9]([C@@H:10]([CH2:18][OH:19])[OH:11])[O:8][C@@H:6]1[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]1[OH:20])[OH:16])[OH:17])=[O:13]
Reactant: NCCCCCCCCCCCCN
Reactant: O=C1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Product: O=C(NCCCCCCCCCCCCNC(=O)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Yield: 22.7 %

Procedure:
2.04 g of cellobiono-1,5-lactone (H. W. Diehl et al., Carbohydr. Res. 38, 364 (1974)) are reacted with 0.60 g of 1,12-diaminododecane analogously to Example 5 and 0.60 g of the title compound are obtained.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27]OC1C=CC(F)=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]>>[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27][O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]
Reactant: OCc1ccco1
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Product: CCOC(=O)CCCCCCC(CCCC(O)COCc1ccco1)C(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step E, except that an equivalent quantity of furfuryl alcohol is substituted for the 4-fluorophenol of Example 1, Step E.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([CH2:23][O:24]CC2C=CC=CC=2)[O:12][C@@H:11]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=3)[C@@:34]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=3[O:53][CH3:54])([F:45])[C:33]2=[O:55])[C@@H:10]1[O:56][P:57](=[O:74])([O:66]CC1C=CC=CC=1)[O:58]CC1C=CC=CC=1)C1C=CC=CC=1>[Pt]=O.C(OCC)(=O)C>[Cl:52][C:50]1[CH:49]=[CH:48][C:47]([O:53][CH3:54])=[C:46]([C@@:34]2([F:45])[C:35]3[C:40](=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)[N:32]([C@H:11]3[C@H:10]([O:56][P:57](=[O:58])([OH:66])[OH:74])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@@H:13]([CH2:23][OH:24])[O:12]3)[C:33]2=[O:55])[CH:51]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N([C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OP(=O)(OCc2ccccc2)OCc2ccccc2)c2cc(C(F)(F)F)ccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2OP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask containing Phosphoric acid dibenzyl ester 4-(S),5-(S)-bis-benzyloxy-6-(R)-benzyloxymethyl-2-(R)-[3-(S)-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-yl]-tetrahydro-pyran-3-(R)-yl ester (3-(S)-IX) (0.117 g, 0.11 mmol) was added ethyl acetate (1 mL). Platinum oxide (0.013 g, 0.06 mmol) was added to the reaction mixture which was then placed under a hydrogen atmosphere. The reaction was allowed to stir at room temperature overnight. The crude reaction mixture was purified via reverse phase column chromatography (C18, 1:1 water:acetonitrile). The title product was obtained as a white solid (0.045 g, 68%). 1H NMR (MeOH-D4, 400 MHz): δ 7.72 (d, 1H, J=1.8 Hz), 7.5 (s, 1H), 7.38 (dd, 1H, J=6.2 Hz, 2.6 Hz), 7.29 (dd, 1H, J=21.7 Hz, 7.7 Hz), 6.93 (dd, 1H, J=7.7 Hz, 1.1 Hz), 5.61 (d, 1H, J=9.4 Hz), 3.97 (d, 1H, J=11.9 Hz), 3.77 (m, 2H), 3.57 (s, 3H); 19F NMR (MeOH-D4, 376 MHz): δ−64.5, −163.3; 31P NMR (MeOH-D4, 161 MHz): δ 1.54; LRMS: 599 [M−H]−.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:41][N:40]=[N:39][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[C:50]([O:54][C:55](=[O:58])[CH2:56][Zn+])([CH3:53])([CH3:52])[CH3:51].C(OCC)C>CCOC(C)=O>[C:9]([NH:8][C:5]1[N:6]=[N:7][C:2]([CH2:56][C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:58])=[CH:3][CH:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)nn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1ccc(NC(=O)C(C)(C)C)nn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of N-(6-bromopyridazin-3-yl)pivalamide (2.00 g, 7.75 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.222 g, 0.465 mmol), and tris-dipalladium(dibenzylideneacetone) (0.213 g, 0.232 mmol) was flushed with nitrogen for 30 min. THF (20 mL) was added, followed by a 1.0 M solution of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in diethyl ether (38.7 mL, 19.4 mmol) and the reaction was sealed and stirred for 2 h at 50° C. An additional amount of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (15.5 ml, 7.75 mmol) was added and the mixture stirred for 2 h at 50 C. The resulting mixture was diluted with EtOAc and filtered, then washed with water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated. MPLC (3−>30% EtOAc:Hex) provided title compound. LC-MS (IE, m/z): 294 [M+1]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C(Cl)(Cl)(Cl)Cl>[CH3:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Br:8])=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1COc1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1COc1ccc(Br)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
NBS (1.46 g, 8.23 mmol) was added to a solution of 31.1 (1.59 g, 7.48 mmol) in carbon tetrachloride (8 mL). The reaction was stirred at 60° C. overnight and filtered to remove succinimide. The filtrate was concentrated in vacuo and purified via radial chromatography (15% diethyl ether in hexanes) to yield 0.65 g (25%) of 2-(2-methyl-benzyloxy)-5-bromotoluene (31.2). LC/MSD m/e: 314.2 (M+Na).