Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:24]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][C:22]=4[F:23])[N:19]=[CH:18][CH:17]=[CH:16]5)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[N:27]1)[CH3:25]
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCn1cc(-c2ccc3ncc(C(O)c4cc5cccnc5cc4F)n3n2)cn1

Procedure:
The title compound was prepared in analogy to Example 9 using (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (Stage 174.3) instead of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1) and 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (tR 3.38 min (conditions 3), MH+=389.2).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[O:4][CH:3]=1.[OH:13]P([O-])(O)=O.[K+]>C1COCC1.CC(O)(C)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[O:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cc2c(Br)coc2cn1
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Br)coc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
3-Bromofuro[2,3-c]pyridine-5-carbaldehyde (3.26 g, 14.42 mmol) is dissolved in THF (100 mL)/t-BuOH (50 mL)/H2O (50 mL), treated with a single portion of NaOCl2 (4.89 g, 43.3 mmol) and KH2PO4 (3.92 g, 28.8 mmol) and stirred at rt for 18 h. The white solid is collected via filtration and the filtrate is concentrated in vacuo to dryness. The residue is suspended in water (25 mL), acidified to pH 2 with concentrated HCl and the resulting solid collected via filtration. The collected solids are dried in a vacuum oven at 50° C. for 18 h and combined to afford 3.52 g (99%) of 3-bromofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (EI) m/z: 241 (M+).
Reaction SMILES: [OH:1][C:2]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH:23]2[CH3:29])([CH:9]1[O:14][CH2:13][C:12](=O)[N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:1][C:2]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH:23]2[CH3:29])([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1CCc2ccc(OC(O)(c3ccccc3)C3CN(C(C)C)C(=O)CO3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCc2ccc(OC(O)(c3ccccc3)C3CN(C(C)C)CCO3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
After mixing 2.5 g. of 2-(1-hydroxy-3-methyl-1-phenyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine, 100 ml. of tetrahydrofuran, and 1.0 g. of lithium aluminum hydride under ice-cooling, the mixture was stirred for 18 hours at room temperature and then 1 ml. of water, 1 ml. of 15% sodium hydroxide aqueous solution, and then 3 ml. of water were added to the mixture followed by stirring for 30 minutes. The mixture was then filtered and the filtrate recovered was dried under reduced pressure. The residue formed was adsorbed on a silica gel column prepared from 50 ml. of silica gel in chloroform and then eluted using ethyl acetate as the eluent. After removing the first 5 ml. of the ethyl acetate eluate emerging from the column, 150 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 2.0 g. (yield 83.0%) of 2-(1-hydroxy-3-methyl-1-phenyl-5-indanyloxymethyl)-4-isopropylmorpholine.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>O=P(Cl)(Cl)Cl>[Cl:15][CH:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:13])([CH3:1])[NH:7]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(C)NC(=O)c2ccccc2O1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)NC(Cl)c2ccccc2O1
Reaction time: 2 h

Procedure:
A solution of 2,2-dimethyl-4-keto-1,3-benzoxazine (1.77 g, 10.0 mmol) and PCl5 (2.09 g, 10.0 mmol) in POCl3 (3.0 mL) was stirred at RT for 1 h then at 50-60° C. for 2 h. The reaction was concentrated and the product distilled (90-95° C./2-3 mm Hg) to afford 4-chloro-2,2-dimethyl-3H-1,3-benzoxazine. (0.496 g, 25%) as a clear oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.58 (d, 1H), 7.48 (m, 1H), 6.97 (m, 1H), 6.94 (d, 1H), 1.63 (s, 6H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][S@](C(C)(C)C)=O)[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)(C(C)(C)C)(C)C.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[NH2:18][C@@H:10]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)[CH2:9][OH:8]
Reactant: Cc1ccnc([C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccnc([C@H](N)CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106 %

Procedure:
(S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.10 g, 2.97 mmol) was dissolved in MeOH (15 ml), and treated with 3.7 ml of a 4.0 M hydrogen chloride solution in dioxane. The reaction was stirred at ambient temperature for 2 hours, concentrated to dryness, and stored under high vacuum overnight to provide 0.71 g (106%) of crude (S)-2-amino-2-(4-methylpyridin-2-yl)ethanol dihydrochloride which was used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[F:9][C:10]([F:35])([F:34])[C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[N:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:27]([C:24]1[N:25]=[N:26][C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[C:10]([F:35])([F:34])[F:9])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1)=[O:28]
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: NCCc1cccs1
Product: O=C(NCCc1cccs1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 24, making variations only as required to use 2-thiophen-2-yl-ethylamine in place of 2,2-(dimethylcyclopropyl)methylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (40% yield). 1H NMR (300 MHz, CDCl3) δ 8.01, 7.73, 7.58, 7.34, 7.12, 6.98, 6.90, 6.84, 4.03, 3.89-3.55, 3.33, 3.12. 13C NMR (75 MHz, CDCl3) δ 167.6, 163.1, 160.0, 145.2, 141.1, 134.2, 132.4, 129.5, 127.2, 127.0, 126.9, 125.3, 123.9, 121.8, 112.5, 46.4, 44.6, 44.4, 41.3, 40.9, 30.9. MS (ES+) m/z 490.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH3:20])=[N:12][C:13]3[N:14]([N:17]=[CH:18][N:19]=3)[C:15]=2[NH2:16])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>CC#N>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:16][C:15]1[N:14]2[N:17]=[CH:18][N:19]=[C:13]2[N:12]=[C:11]([CH3:20])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=2)=[O:30])=[CH:3][CH:4]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cc1nc2ncnn2c(N)c1C#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2ncnn2c(N)c1C#Cc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of Example 1 (10 mg, 0.038 mmol) in 1.0 mL of CH3CN was added 3-chloro-phenyl isocyanate (6.4 mg, 0.046 mmol) and triethylamine (8 μL, 0.057 mmol). The resulting mixture was stirred for over night at room temperature. The resulting mixture was purified by reverse phase HPLC (C-18 column, eluting with a 5-100% CH3CN gradient in 0.1% trifluoroacetic acid) to the title compound as its trifluoroacetic acid salt (3.5 mg, 17.3% yield). MS (ESI) m/z 416, 418 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc2c(c1)[C@@H](OCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[C@@H](OCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
To a solution of the title compound of Step 3 (62.7 mg, 0.175) in 1.00 ml of THF was added 1.00 ml of 6 N NaOH and 1.00 ml MeOH. The resulting mixture was stirred overnight. The mixture was acidified to neutral pH, concentrated and the title compound was purified on a Biotage MPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][N:16]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[S:17]([CH3:20])(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:16]([CH3:15])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:22][CH:23]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CN(c1ccc(C(=O)O)cc1)S(C)(=O)=O
Product: CN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)S(C)(=O)=O

Procedure:
500 mg of methyl 4-(methylamino)benzoate was cooled to 0° C. in DCM with 270 μL of Pyridine before 260 μL Methanesulfonyl Chloride was added dropwise. Reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crude material was dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-methylmethylsulfonamido)benzoate. 698 mg of methyl 4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to give 4-(N-methylmethylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 416.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(O)C.O.CN(C)C(=O)C>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (3.0 g, 17 mmols), benzenesulfonyl chloride (3.0 g, 17 mmols) and N,N-dimethylacetamide (30 ml) was stirred at room temperature for 2 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure. A 1 N sodium hydroxide solution (50 ml, 50 mmols) was added to a solution of the residue in tetrahydrofuran (50 ml) and ethanol (50 ml). The resulting mixture was stirred at 60° C. for 1 hour. Water was added to the reaction mixture, which was acidified with potassium hydrogensulfate added thereto, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was crystallized from hexane/ethyl acetate to give a solid of 4-benzenesulfonylaminophenylacetic acid (3.1 g, 64%).
Reaction SMILES: CC(C)(C)C([O:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[O:24]C(=O)C(C)(C)C)[C@H:16]2[C@H:7]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:31])[CH2:15]2)=O>CO>[OH:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[OH:24])[C@H:16]2[C@H:7]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:31])[CH2:15]2
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@H]2[C@@H]3CC(=O)c4ccccc4[C@H]3[C@H](OC(=O)C(C)(C)C)C[C@]12C
Solvent: CO
Product: C[C@]12C[C@@H](O)[C@@H]3c4ccccc4C(=O)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 74.4 %

Procedure:
Hydrolysis of the keto diester (16A) (158 mg) in the above manner gave the keto diol (5A) (74 mg, 74%), m.p. 205°-208° C. (from methanol, νmax 3600 (OH) and 1680 cm-1 (C=O), δ (250 MHz) 8.13 (1 H, dd, J 8 and 0.5 Hz, aromatic proton), 8.04 (1 H, dd, J 7 and 1,5 Hz, aromatic proton), 7.56 (1 H, dt, J 8 and 1.5 Hz, aromatic proton), 7.36 (1 H, dt, J 7 and 0.5 Hz, aromatic proton), 4.32 (1 H, ddd, J 10.5, 9.5, and 5 Hz, 11-proton), 3.79 (1 H, t, J 8 Hz, 17-proton), 2.77 (1 H, dd, J 17 and 3.5 Hz, 7-proton), 2.5 (1 H, t, J 10.5 Hz, 9-proton), 2.41-1.22 (11 H, m), 0.79 (3 H, s, 18-CH3), (Found: M 286.1572. C18H22O3 requires M 286.1567).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1.NC1C=CC=CC=1.[C:30]([C:32]1[O:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)#[N:31].C(Cl)(=O)C(Cl)=O.ON1C(=O)CCC1=O.CCN(C(C)C)C(C)C>[Pd].C1COCC1.ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[NH:14][C:37]([C:35]2[O:36][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[O:38])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(N3CCOCC3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCOCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Reaction time: 1 h
Yield: 65 %

Procedure:
The procedure of Example 4, step (c) was followed using 101 mg (0.331 mmol) of 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-morpholine (as prepared in the previous step) and 40 mg of 10% palladium on carbon (50% by weight water) in 5 mL THF to prepare the corresponding aniline. However, 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was used to acylate the aniline instead of 5-cyanofuran-2-carbonyl chloride. (5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was previously prepared from 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), oxalyl chloride, N-hydroxysuccinimide and DIEA following the procedure of Example 4, step (c).) The aniline prepared above in 3.0 mL of anh dichloromethane was treated with 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester. After stirring for 1 h, an additional 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was added. After 3 h, a final 77.5 mg (0.331 mmol) of 5-cyanofuran-2-carboxylic acid N-hydroxysuccinimide ester was added and the mixture stirred 18 h. Concentration in vacuo and chromatography on a 10-g silica SPE column with 2-4% EtOAc-dichloromethane afforded 85.1 mg (65%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.22, 7.26 (AB q, 2H, J=3.7 Hz), 6.78 (d, 1H, J=2.7 Hz), 6.71 (dd, 1H, J=8.9, 2.7 Hz), 3.86-3.88 (m, 4H), 3.13-3.15 (m, 4H), 2.98-3.01 (m, 2H), 2.70-2.15 (m, 2H), 1.83-1.86 (m, 2H), 1.5-1.7 (br m, 1H) and 1.43-1.53 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H26N4O3, 395.2 (M+H), found 395.2.
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[NH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].[F:19][C:20]([F:26])([F:25])[C:21](OC)=O>CO>[NH2:14][C:13]1[N:12]=[C:10]([NH:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:11]=[C:21]([C:20]([F:26])([F:25])[F:19])[N:15]=1
Reactant: COC(=O)C(F)(F)F
Reactant: N=C(N)NC(=N)NCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc(NCc2ccccc2)nc(C(F)(F)F)n1
Temperature: 0 °C

Procedure:
To benzylbiguanide hydrochloride (11.3 g., 0.05 mole) in methanol (270 ml.) is added powdered sodium methoxide (5.4 g., 0.1 mole) followed by methyl trifluoroacetate (6.4 g., 0.05 mole) dropwise with stirring. The solution is stirred at room temperature for 64 hours, then poured into ice-water (500 ml.) and a white solid precipitated and is filtered off, m.p. 183°-185°C. Crystallization from acetonitrile affords colorless cubic crystals, m.p. 184°-185°C. Yield 8 g. (60%)
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:10]2=[O:25])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:10]2=[O:25])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CNS(C)(=O)=O)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.543 mmol) in DCM (10 ml) cooled to 0° C., TFA (0.418 ml, 5.43 mmol) was added drop wise, and the solution stirred at room temperature for 24 hours. The solvent was removed under vacuum and dried to give 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetic acid as a yellow solid (0.170 g, 0.544 mmol, yield considered to be quantitative, MS/ESI+ 312.9 [MH]+). This product was used without any further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]C)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:45]>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:45])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCc1nnc(S(=O)Cc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-butyl-4-[[4-[1-(carbomethoxy)-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 1, Step F) in dry CH2Cl2 is treated with m-chloroperoxybenzoic acid (1 equivalent), and the resulting mixture is stirred at room temperature for about 30 minutes or until TLC indicates complete reaction. At this point the mixture is partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase is washed repeatedly with saturated NaHCO3, then dried over MgSO4, filtered, and concentrated. The residue may be purified by chromatography on silica gel to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>N1C=CC=CC=1>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Nc3nccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To 4′-Nitro-biphenyl-4-sulfonyl chloride (1.0 g, 3.2 mmol), dissolved in pyridine (5.0 ml) was added 2-aminothiazole (1.6 g, 16.0 mmol) and the mixture was stirred at rt for 72 h. Pouring the reaction mixture into ice-water gave a precipitate that was filtered and dried to obtain 4′-Nitro-biphenyl-4-sulfonic acid thiazol-2-ylamide (0.6 g, 53%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=362.2; tR=2.95 min.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.F[B-](F)(F)F>>[C:2]1([CH:1]=[CH:8][CH:9]([OH:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1
Agent: F[B-](F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC(O)C=Cc1ccccc1
Yield: 26.4 %

Procedure:
In a 100 ml stainless steel autoclave were charged 5 g (34.2 mmole) of benzalacetone and 0.204 g (0.171 mmole) of ##STR25## ((+)-BINAP)}BF4 synthesized in Example 1, and the mixture was allowed to react in the same manner as in Example 12 to obtain 1.34 g of 4-phenyl-3-buten-2ol having a purity of 70% and an optical purity of 70.3 %ee at a conversion of 26.7%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:22]([C:19]2([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH2:21][CH2:20]2)=[O:23])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Yield: 167.5 %

Procedure:
A solution of piperidine-3-carboxylic acid ethyl ester (10.0 g, 0.032 mol), 1-(4chloro-phenyl)-cyclopropylcarboxylic acid (9.57 g, 0.049 mol), diisopropylethyl amine (21.0 g, 0.16 mol) in dichloromethane (160 mL) was stirred at room temperature. PyBroP (22.6 g, 0.49 mol) was added and the reaction mixture continued stirring at room temperature. After 12 h the reaction mixture was quenched with 10% KOH. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The crude material was purified using silica gel chromatography (80:20 hexane:ethyl acetate) to yield the amide (18.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C@@H:19]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]C)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)[CH2:8][CH2:7]1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C@@H:19]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)[CH2:10][CH2:11]1
Reactant: COC(=O)[C@H](Cc1ccccc1OC)N1CCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1O)N1CCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(αS) Methyl 4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-α-[(2-methoxyphenyl)methyl]-1-piperidineacetate (120 mg) in dichloromethane (6 mL) was cooled to −78 C under nitrogen, and a 1M solution of boron tribromide in dichloromethane (9 mL) was added dropwise to it. The mixture was then stirred at −78° C. for 30 minutes, and then at −5° C. for 30 minutes. The reaction mixture was then quenched carefully with methanol (20 mL), allowed to warm to room temperature and the volatiles removed in. vacuo. The residue was purified by reverse-phase HPLC using 75:25 to 5:95 0.1% aqueous ammonium acetate/acetonitrile over 6 minutes, symmetry column. This gave 67 mg of the title compound as an oil.