Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1cccc(-c2ccccc2)c1

Procedure:
3-Bromophenol (1.0 g, 5.78 mmol), phenylboronic acid (1.4 g, 11.48 mmol), potassium carbonate (2.0 g, 14.47 mmol), and PdCl2(PPh3) (1/200 eq.) were added to a solution of dioxane/H2O (20 mL/5 mL). The resulting solution was refluxed for 16 h. The reaction mixture was then partitioned between Et2O and water, and the aqueous phase was extracted with Et2O. The combined organic layer was evaporated to dryness and purified by flash column chromatography (ethyl acetate/hexanes=1/9) to give TC-IV-119 (1.02 g, 100%) as a transparent oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:22]=[N:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][CH:28]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(F)nc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(F)nc4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(6-fluoro-3-pyridyl)benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][N:38]=1>O1CCOCC1.O.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>[CH3:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)ccn1
Temperature: 95 °C
Yield: 19.7 %

Procedure:
A mixture of Example C1 (0.250 g, 0.598 mmol), K2CO3 (0.165 g, 1.197 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.157 g, 0.718 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.069 g, 0.060 mmol), sparged again with Ar and heated at 95° C. for 36 h. The mixture was cooled to RT, treated with satd. NaHCO3 and extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (56 mg, 20%). 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1 H), 8.59 (d, J=5.6 Hz, 1 H), 8.52 (d, J=5.2 Hz, 1H), 8.27 (d, J=3.0 Hz, 1 H), 8.08 (d, J=9.1 Hz, 1 H), 7.89 (s, 1 H), 7.81-7.74 (m, 2 H), 7.70 (d, J=2.4 Hz, 1 H), 6.97 (dd, J=5.6, 2.4 Hz, 1 H), 3.93-3.78 (m, 5 H), 3.49-3.35 (m, 4 H), 2.52 (s, 3 H), 1.77-1.65 (m, 2 H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 475.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:14]1([C@@H:12]([NH:11][CH:10]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH3:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](NC(c1cccc([N+](=O)[O-])c1)c1cccs1)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@H](NC(c1cccc(N)c1)c1cccs1)c1ccccc1
Yield: 9.1 %

Procedure:
In a similar manner to that described in Example (15b), N-[(3-nitrophenyl)-2-thienylmethyl]-N-[(S)-1-phenylethyl]amine (4.56 g) [prepared as described in step (a) above], nickel chloride hexahydrate (6.42 g) and sodium borohydride (2.04 g) were reacted and purified, to afford isomer A of the title compound (936 mg) as a pale yellow oil and isomer B of the title compound (380 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][NH:36][C:15]([CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:31])([F:30])[F:32])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:16]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Temperature: 0 °C
Yield: 98 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid methylcarbamoylmethyl-amide (47 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), methylamine (0.2 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 480.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:22])=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCCCCCCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCC(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To an ice-cold, stirring solution of 3 gm 9(4-methoxyphenyl)nonanoic acid in 10 ml. CH2Cl2 was added dropwise 1.2 ml thionyl chloride. The solution was then allowed to warm up to room temperature. The solvent and excess thionyl chloride were removed in vacuo to give a brown oil, which was used directly in the last step without further purification.
Reaction SMILES: F[C@H]1CCNC1.C(N1CCN(C(=O)CC2C[C@@H](C(N3CC[S:26]C3)=O)NC2)CC1)C.O[CH:31]([CH2:48][CH2:49][C:50]1[CH:55]=CC=CC=1)[C:32]([NH:34][CH2:35][CH:36]1[CH2:40][CH:39]([C:41]([N:43]2[CH2:47][CH2:46][S:45][CH2:44]2)=[O:42])[NH:38][CH2:37]1)=[O:33]>>[S:45]1[CH2:46][CH2:47][N:43]([C:41]([C@H:39]2[NH:38][CH2:37][C@@H:36]([CH2:35][NH:34][C:32](=[O:33])[CH2:31][C:48]3[S:26][CH:55]=[CH:50][CH:49]=3)[CH2:40]2)=[O:42])[CH2:44]1
Reactant: CCN1CCN(C(=O)CC2CN[C@H](C(=O)N3CCSC3)C2)CC1
Reactant: O=C(NCC1CNC(C(=O)N2CCSC2)C1)C(O)CCc1ccccc1
Agent: F[C@H]1CCNC1
Product: O=C(Cc1cccs1)NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1

Procedure:
(2R′, 3S, 5S)-2-Hydroxy-4-phenyl-N-[5-(thiazolidine-3-carbonyl)-pyrrolidin-3-ylmethyl]-butyramide;
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[N:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42](O)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]>CN(C)C=O>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42]([NH:29][C:26]2[CH:27]=[CH:28][N:23]=[N:24][CH:25]=2)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Reactant: Nc1ccnnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2ccnnc2)c1
Temperature: 25 °C

Procedure:
EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 mL, 6.84 mmol) and 4-pyridazinamine (0.49 g, 5.13 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 101; 1 g, 3.42 mmol) in N,N-dimethylformamide (DMF; 25 ml) and the mixture was stirred at room temperature. The DMF was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml) and the organic layer washed with saturated sodium hydrogencarbonate (2×50 ml) and water (2×50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a dark yellow solid. 0.98 g.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]=[C:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]1([C:7](=[N:9][C@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=N[C@@H](C)c1ccccc1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=N[C@H](C)C(F)(F)F)c1ccccc1

Procedure:
To crude (S)-(1-phenylethyl)-(2′,2′,2′-trifluoro-1-methylethylidene)-amine (1410 g, 4.54 mol theory) and washings with 20 g of toluene at room temperature, add DBU (1050 g, 6.897 mol) in portions to keep temperature below 60° C. Heat the reaction at 60° C. overnight (14 h) under nitrogen until the starting material rearranges to the desired intermediate (2460 g of solution). MS (ES+) m/z: 216.2 (M+H)+.
Reaction SMILES: [O:1](N=[N+]=[N-])S(N=[N+]=[N-])(=O)=O.[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]=[N+:26]=[N-:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:12](=[CH2:14])[CH3:13].C(OO)(=O)C.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:25]([S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:11][C:12]2([CH3:13])[O:1][CH2:14]2)=[CH:21][CH:20]=1)(=[O:23])=[O:24])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=NOS(=O)(=O)N=[N+]=[N-]
Reactant: C=C(C)COc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(COc2ccc(S(=O)(=O)N=[N+]=[N-])cc2)CO1
Temperature: 41 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To show another example of the epoxy-sulfonylazide of the instant invention, a solution of p-methallyloxybenzenesulfonylazide (506 parts) in methylene chloride (1,450) parts is stirred and heated to reflux (41° C.) then a solution of 35% peracetic acid in acetic acid (521.5 parts) containing sodium acetate (15.6 parts) is added slowly from an addition funnel over 15 minutes. An additional 40 parts of methylene chloride is added to adjust the reflux temperature to 45° C. After 6 hrs stirring and refluxing at 45° C. the reaction is quenched with 835 parts of distilled water. The layers are separated and the organic phase is washed with 555 parts of 10% sodium sulfite, 835 parts of sodium bicarbonate, and 565 parts of distilled water containing 23 parts of trioctylammonium chloride. The solution is dried azeotropically, and the solvent is removed at 55° C. and 20 mm to yield 528 parts of 3-(p-azidosulfonylphenoxy)-2-methylpropylene oxide as a white, crystalline solid. This represents a yield of 98%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[CH2:11](I)[CH3:12]>CN(C=O)C>[Br:3][C:4]1[O:8][C:7]([CH2:9][O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CCI
Reactant: OCc1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1ccc(Br)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (95%, 19 mg, 0.75 mmol) was diluted in dry DMF (0.5 mL) and cooled to 0° C. A solution of (5-bromo-2-furanyl)methanol (120 mg, 0.68 mmol) was added, and the mixture was stirred for 5 minutes. Ethyl iodide (117 mg, 0.75 mmol) was added, and the mixture was stirred at rt overnight. The reaction mixtures were quenched by the careful addition of water, then extracted with diethyl ether. The combined organics were dried and concentrated. The residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes. The desired fractions were combined and concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:5]1[CH:4]=[CH:3][C:2]([CH2:1][NH:8][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:40][CH:41]=3)=[CH:13][N:12]=2)=[O:18])=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccc(Br)cn1)NCc1ccccc1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 150 °C
Yield: 78.8 %

Procedure:
A 10 mL reaction tube with a septum closure and stir bar was charged with N-benzyl-2-(5-bromopyridin-2-yl)acetamide (123 mg, 0.403 mmol), 4-(2-(4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy)ethyl)morpholine (171 mg, 0.513 mmol), and FibreCat 1007 (30 mg, 0.015 mmol). Ethanol (3 mL) was added, followed by aqueous potassium carbonate solution (0.60 mL, 1.0 M, 0.60 mmol). The tube was sealed and heated under microwave conditions at 150° C. for 10 minutes. The reaction was cooled and concentrated to remove the majority of the ethanol, and then taken up in 10 mL of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO4, filtered and concentrated to a white solid. This white solid was triturated with ethyl ether to give KX2-391 as a white solid (137 mg, 79%): mp 135-137° C.; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=2.0 Hz), 7.81 (dd, 1H, J=2.4 Hz, J=8.0 Hz), 7.65 (br s, 1H), 7.49 (d, 2H, J=8.8 Hz), 7.37-7.20 (m, 6H), 7.01 (d, 2H, J=8.8 Hz), 4.49 (d, 2H, J=5.8 Hz), 4.16 (t, 2H, J=5.7 Hz, 3.82 (s, 2H), 3.78-3.72 (m, 4H), 2.84 (t, 2H, J=5.7 Hz), 2.62-2.58 (m, 4H); HPLC (Method B) 98.0% (AUC), tR=1.834 min.; APCI MS m/z 432 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1>CCOC(C)=O>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])([CH3:1])[CH3:18])=[CH:13][CH:12]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(-c2ccccc2Br)cc1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(-c2ccccc2Br)cc1

Procedure:
Prepared according to the general procedure Cer-1 using methyl magnesium bromide and ketone from step 1 as starting material. Flash chromatography (Hex:EtOAc; 90:10) afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])[CH:4]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)OC(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
4-(trifluoromethyl)pyridin-2-amine (1.0 g, 6.17 mmol) was dissolved in THF (20 mL) and treated with pyridine (600 μL, 7.4 mmol) and isopropenyl chloroformate (596 μL, 6.17 mmol). The reaction was stirred at rt for 6 h. The reaction was then concentrated and triturated with EtOAc. The crude residue was purified by MPLC (100% CH2Cl2) to yield a pale yellow solid (1.2 g, 79%); 1H-NMR (DMSO-d6) δ 11.0 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.45 (d, J=5.5 Hz, 1H), 4.81 (t, J=1.1 Hz, 1H), 4.76 (s, 1H), 1.94 (s, 3H).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:42]=[CH:41][C:40]([F:39])=[C:45]([F:46])[CH:44]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(F)c2)c1

Procedure:
5-(tert-Butyl)-3′,4′-difluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3,4-difluorophenylboronic acid.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26][OH:27])[OH:25])[OH:23])[OH:21])[OH:19]>>[OH:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]1[O:19][C@:24]([OH:25])([CH2:26][OH:27])[C@@H:22]([OH:23])[C@@H:20]1[OH:21]
Reactant: OCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O

Procedure:
The process of claim 1 in which D-glucose is aminated to N-(2-hydroxyethyl) glucamine which in turn is oxidized to produce 6-(2-hydroxyethyl)amino-6-deoxy-α-L-sorbofuranose which is then reduced to produce N-(2-hydroxyethyl)-1-deoxynojirimycin.
Reaction SMILES: O[C:2]1([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([C:2]5[CH:3]([CH3:7])[O:4][CH2:5][CH:6]=5)=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: CC1OCCC1(O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1OCC=C1c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
6-(3-Hydroxy-2-methyltetrahydrofuran-3-yl)-3-[4-(4-methyl[1,4]diazepan-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one and p-toluenesulfonic acid were reacted by method AA. The product with the molecular weight of 422.55 (C23H26N4O2S) was obtained in this way; MS (ESI): 423 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([N:37]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:36])[CH2:27]1>>[CH:44]1([N:37]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[C:35](=[O:36])[CH2:34][C@H:28]2[CH2:27][C@@H:26]([CH2:25][CH2:24][N:23]3[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:31][C:30]([CH3:33])([CH3:32])[O:29]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(C2CCCCC2)C2CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(C2CCCCC2)C2CCCCC2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the tiotle compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dicyclohexylacetamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:19])[CH:3]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:19])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nnc(Cl)cc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1nnc(Cl)cc1C
Temperature: 137.5 °C
Reaction time: 0.67 h
Yield: 67.2 %

Procedure:
1.81 g of diethyl (6-chloro-4-methyl-3-pyridazinyl)malonate and 15 ml of dimethyl sulfoxide were mixed. To the mixture was added 0.45 g of sodium chloride and 0.23 g of water. The mixture was stirred for about 40 minutes at an inner temperature of 125 to 150° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 1.05 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.91 g of ethyl (6-chloro-4-methyl-3-pyridazinyl)acetate.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:15])[CH3:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(=O)[C@@H](N)C(C)(C)C
Reaction time: 16 h
Yield: 303.5 %

Procedure:
To a solution of (1(S)-acetyl-2,2-dimethylpropyl)carbamic acid-tert-butyl ester (700 mg, 2.55 mmol) in dichloromethane (10 mL) at 0° C. was added trifluoroacetic acid (5 mL). The reaction was left at <5° C. for 16 hours before the solvents were removed in vacuo to give a bright yellow oil. The residue was dissolved in methanol (30 mL) and was treated portionwise with Dowex 1X8-400 basic resin until pH 9. Filtration and removal of the solvents in vacuo gave the title compound as a pale yellow oil (˜1.0 g, >100%, residual water). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-methoxy-phenyl)-amide as a white solid. (Yield 45 mg, 64%).