Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([CH3:31])=[CH:24][C:23]=1[Cl:32]>>[Cl:32][C:23]1[CH:24]=[C:25]([CH3:31])[C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[NH:11][C:10]1[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1
Reactant: Cc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])c(C)cc1Cl)OCC

Procedure:
Analogously to Example 13A/Step 1, from two reactions (273 mg and 1.58 g; 6.72 mmol in total) of the compound of Example 4A and 250 mg and 1.45 g (7.4 mmol in total) of 1-bromo-2-chloro-4-methyl-5-nitrobenzene gave, after 2 h of heating under reflux, a crude product which was purified by double chromatography on a Biotage system (in each case 50 g Snap column; mobile phase gradient hexane/ethyl acetate, from 20% ethyl acetate increasing rapidly to 100% ethyl acetate, then ethyl acetate/methanol, increasing slowly to 100% methanol). This gave 1.96 g (69% of theory) of the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:1].[C:28]1([P+:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:2][C:3]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1cc(CBr)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1[N+](=O)[O-]
Product: [Br-]
Yield: 70.2 %

Procedure:
A mixture of 15 g (57.7 millimoles) of 3-bromomethyl-6-nitro-benzoic acid, 15.17 g (57.7 millimoles) of triphenyl phosphine and 70 ml anhydrous toluene is refluxed for 2 hours. The precipitated product is filtered off, washed with ether and dried. Thus 21.15 g of the title compound are obtained, yield 71%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)[C:12](=[O:25])[CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 mg (0.45 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one in 5.0 mL DCM is added 186 μL (1.34 mmol) triethylamine and subsequently 69 μL (0.89 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and 74 μL (0.89 mmol) pyrrolidine is added. The mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:44]([O-:46])=[O:45])=[C:33]([CH:35](C(OC)=O)[C:36]([O:38]C)=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:44]([O-:46])=[O:45])=[C:33]([CH2:35][C:36]([OH:38])=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(C(=O)OC)C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(CC(=O)O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 55 °C
Yield: 75 %

Procedure:
To a stirred solution of dimethyl 2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)malonate (10.0 g, 15.3 mmol) in 1:1:1 THF/MeOH/water, was added 3N aqueous NaOH (20 mL). The resulting mixture was heated at 55° C. for 15 h. The reaction mixture was cooled to room temperature and treated with 5N aqueous HCl to pH 5. The aqueous layer was extracted with ethyl acetate (3×30 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was triturated with methanol and ether and the solid collected by filtration to give the title compound in 75% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.52 (br. s., 1H) 8.49 (q, J=4.23 Hz, 1H) 8.09-8.15 (m, 1 H) 8.02 (s, 1H) 7.96 (d, J=3.32 Hz, 4H) 7.31-7.44 (m, 4H) 7.25 (s, 1H) 3.98 (s, 2H) 3.56 (s, 3H) 2.84 (d, J=4.69 Hz, 3H) 1.94-2.03 (m, 1H) 0.85 (d, J=3.13 Hz, 3H) 0.48 (br. s., 1H). LCMS (m/z, ES+)=583 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[F:25])[C:11](=[O:26])[CH:10]=1)C1C=CC=CC=1>[Pd].C(Cl)Cl.CO.C1COCC1>[F:25][C:16]1[CH:17]=[C:18]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:19]=[CH:20][C:15]=1[N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:26]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)c(F)c1
Reaction time: 1.75 h
Yield: 107.8 %

Procedure:
To a 1 liter recovery flask added 10% palladium on carbon (1.75 g, 16.44 mmol), applied vacuum for 5 minutes then vented to nitrogen. Added 20 mL each of CH2Cl2/MeOH/THF to wet solid, then added a suspension of 4-(benzyloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (5.38 g, 14.41 mmol) in ˜80 mL each of CH2Cl2/MeOH/THF (total of 100 mL each solvent), all while keeping a nitrogen flow over mixture. Applied vacuum briefly then placed under an atmosphere of hydrogen for 105 minutes, filtered through a 60×60 mm pad of CELITE® 545 filter aid using an additional 200 mL each of MeOH and CH2Cl2, and concentrated the filtrate to give 4.4 g of crude product as an off-white powder. MS (ESI) 284.3 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.ClC(Cl)(Cl)C(=N)O[C:33]([CH3:36])([CH3:35])[CH3:34]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)(C)OCCCc1c[nH]cn1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 10 mmol of tert-butyl trichloroacetimidate are treated as described in Example 116. The title compound is crystallized in the form of the hydrogen maleate in ethanol and diethyl ether.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[S:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])[N:8]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (75 mg, 0.229 mmol), thiophene-3-carbonyl chloride (44.9 mg, 0.306 mmol) and triethylamine (42.5 μl, 0.306 mmol) were combined in CH2Cl2 (4 ml) and stirred 10 min. at 25° C. The reaction was concentrated and chromatographed on silica gel (2% MeOH in CH2Cl2) to give the title compound as a white solid from Et2O: (m.p. 238°-239°).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](Cl)=[O:13])[CH2:8][CH2:7]1.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH2:8][CH2:7]1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CN1CCC(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Yield: 84 %

Procedure:
To a cooled suspension of anhydrous aluminum chloride (20 g, 75 mmol) in benzene 30 ml at 0° C. was added 1-methylpiperidine-4-carboxylic acid chloride in small portions and the resulted mixture was refluxed for 3 hours. The reaction mixture was cooled down, poured-into ice water. The organic phase was discarded. The aqueous solution was washed with 2×50 ml ethyl ether, basified with potassium hydroxide pellet slowly to pH >10 and extracted with ethyl ether 4×50 ml. The combined ethereal solution was dried over sodium sulfate and concentrated to give 9.5 g of the title compound in 84% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[C:5]2[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:4]=2[O:3]1.O1CCCC1.[H][H]>CO.[C].[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:4]=3[O:3][C:2]([CH3:1])([CH3:27])[C:7]2=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2cccc([N+](=O)[O-])c2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2cccc(N)c2)C1=O

Procedure:
To a solution of N-[2,2-dimethyl-4-(3-nitrophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 146; 240 mg) in methanol (5 mL)-tetrahydrofuran (5 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give N-[4-(3-aminophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-methanesulfonamide as a colorless powder.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[N:11]1([C:16](N2C=CN=C2)=[S:17])[CH:15]=[CH:14][N:13]=[CH:12]1>C(#N)C>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10][C:16]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[S:17]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2c(s1)CCCC2
Solvent: CC#N
Product: S=C(Nc1nc2c(s1)CCCC2)n1ccnc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (0.5 g, 3.24 mmol) in acetonitrile (20 mL) was added di(1H-imidazol-1-yl)methanethione (0.58 g, 3.24 mmol). The reaction was stirred at 50° C. for 4 hours. The reaction was cooled and concentrated to yield crude product. The crude material was purified via flash chromatography (50-100% ethyl acetate-hexane) to yield N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.60 g, 2.27 mmol, 70.0% yield) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1cccc(F)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(F)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.70-7.59 (2H, m), 7.45-7.17 (11H, m), 6.41 (1H, br.s), 3.47-3.37 (2H, m), 2.77-2.73 (2H, m), 2.27 (3H, s), 2.21 (3H, s).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=1[O:23][CH3:24].CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: COc1cc(CN)ccc1F
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)c2ccc(S(=O)(=O)Cl)cc2)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
Dissolve 4-chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) in THF (25 mL) and cool to −78° C. Slowly add a pre-mixed solution of 4-fluoro-3-methoxybenzyl-amine (1.91 g, 12.3 mmol), Et3N (1.64 mL, 11.8 mmol), and DMAP (150 mg, 1.23 mmol) in THF (25 mL) to the above cooled solution over 1 h. Stir the resulting mixture at −78° C. for 1 h, then warm to RT and stir for 4 h. Remove all solids by filtration and wash with THF (5 mL). Concentrate the filtrate and re-dissolve the crude material in EtOAc (30 mL) and wash with 1N HCl (30 mL). Separate the organic and aqueous layers and extract the aqueous phase with additional EtOAc (30 mL). Combine the organic solutions dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes) to give the title compound as a white solid (1.36 g, 28%). MS (ES−) 356.1 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 2H, J=8.3), 8.00 (d, 2H, J=8.8), 7.05 (dd, 1H, J=8.2, 11.1), 6.96 (dd, 1H, J=1.9, 8.0), 6.86 (m, 1H), 6.44 (br s, 1H), 4.61 (d, 2H, J=5.7), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[CH:4][S:5][C:6]=1[CH3:7].Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Br)(C)C>C1COCC1.CC1CCCO1>[CH3:16][O:15][N:14]([CH3:13])[C:8]([C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=1)=[O:10]
Reactant: COC(=O)c1csc(C)c1C
Reactant: CNOC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CON(C)C(=O)c1csc(C)c1C
Temperature: 0 °C
Yield: 80.9 %

Procedure:
To a cooled (−30° C. to −20° C.) slurry of methyl 4,5-dimethylthiophene-3-carboxylate (5.44 g, 32.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.80 g, 49.2 mmol) in THF (45 mL) at was added slowly (over 15 min) a solution of isopropylmagnesium bromide (3.85 mL, 11.16 mmol, 2.9 M) in 2-methyl-tetrahydrofuran. After complete addition of the base, the reaction mixture was warmed to 0° C. and partitioned between 1 N HCl (55 mL) and MTBE (50 mL). The aqueous phase was extracted with MTBE (2×) and the combined organic layer was washed with water (until the pH of the aqueous was ˜5). The organic layer was dried over Na2SO4 and concentrated to give a light yellow oil. The crude product was purified on Biotage system (gradient elution 7% EtOAc:93% Hexanes to 60% EtOAc:40% Hexanes) to give the titled compound as a yellow oil (5.17 g, 25.9 mmol, 81% yield). LC/MS m/z 200 [M+H]+.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1.C(N(C(C)C)C(C)C)C>O>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:5])[CH:13]=3)[CH2:19][CH2:20]2)=[CH:30][C:31]=1[F:37])#[N:34]
Reactant: N#Cc1ccc(OCCCCl)cc1F
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)c(F)c3)CC2)cc1F
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
To a dimethylsulfoxide (4.0 mL) solution of 0.26 g of 2-fluoro-4-[3-(4-piperidinyl)propoxy]benzonitrile and 0.21 g of 4-(3-chloropropoxy)-2-fluorobenzonitrile was added 0.88 mL of N-ethyldiisopropylamine, which was then stirred at 80 to 90° C. for 8 hours and 15 minutes. The reaction mixture was cooled down to room temperature, to which water was then added, followed by extraction with ethyl acetate. The extract was washed twice with water and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=10:1) to provide 0.25 g of 4-(3-{1-[3-(4-cyano-3-fluorophenoxy)propyl]-4-piperidinyl}propoxy)-2-fluorobenzonitrile as brown solid form.
Reaction SMILES: [C:1]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23](C=O)[CH:22]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-:30].[K+].OO>C(O)(C)C.O>[C:1]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:30])[CH:22]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCc1ccc(O)c(C=O)c1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCCc1ccc(O)c(O)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
The aldehyde from example 2 (23.6 g, 58.5 mmole mmole) was dissolved in 100 mL of isopropyl alcohol at 45° C. The solution was cooled to 35° C. and 8.8 g of 45% KOH (70 mmoles) in 150 mL of water was dripped in at 30-35° C. The solution was cooled 20-25° C. and a solution of 8 g of 35% hydrogen peroxide (82 mmole) in 10 mL of water was dripped in over about 20 min at 20-25° C. A mild exotherm was noted, but the temperature was easily held by a water bath. The product precipitated during the addition of the peroxide. The slurry was held 1 hr at which time it exhibited a weak peroxide test (starch-iodide paper). Acetic acid (2mL) was added to reduce the pH from ca. 8 to ca. 6. The slurry was filtered, washed with water, and the product was air-dried to give 20.8 g (91%) of white solid. HPLC analysis indicated an area % product of 93.6, the melting point was 61-62° C., and the H1 NMR was consistent with the structure. The composition of Example 3 prior to isolation by HPLC: 91% product, 1% formate ester 9, 3% starting material.
Reaction SMILES: [CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C@@:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[CH2:10][C@H:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCOc1ccc(OCc2ccccc2)cc1
Reactant: O[C@@H]1CNCC[C@]1(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@]1(O)Cc1ccccc1
Temperature: 90 °C
Yield: 100 %

Procedure:
To a solution of 5.0 g (24 mmol) (3R,4R)-4-benzyl-3,4-dihydroxy-piperidine in 150 ml DMF were added 7.4 g (24 mmol) 1-benzyloxy-4-(2-chloro-ethoxy)-benzene and 5.0 g (36 mmol) K2CO3 and the reaction mixture was heated to 90° C. for 72 hours. After the addition of water the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 10.5 g (24 mmol, 100%) (3R,4R)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([NH:18][C:19](=[O:29])[CH:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:21])[CH3:17].O>O1CCOCC1.CO>[CH2:16]([NH:18][C:19](=[O:29])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)=[CH:24][CH:23]=1)[CH3:21])[CH3:17]
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(-c2ccncc2)cc1
Reaction time: 48 h

Procedure:
Under inert gas atmosphere 36 mg (0.049 mmol) PdCl2(dppf)xCH2Cl2, 28 mL (56 mmol) 2N sodium carbonate solution and 3.35 g (27.2 mmol) pyridine-4-boronic acid are added to 7.50 g (24.7 mmol) N-ethyl-2-(4-iodo-phenyl)-propionamide (V1.1) in 45 mL 1,4-dioxane and 15 mL methanol. The mixture is stirred for 2 d at reflux. After that time, water is added and the mixture is extracted with EtOAc (2×). The combined organic layers are washed with water and 150 mL 1N HCl are added. The aq. layer is separated, filtered and alkalized with 1N NaOH. The precipitate is filtered off and dried.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.[F:15][C:16]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:17](OCC)=[O:18].CCOCC.CCCCCC>CCO>[F:15][C:16]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:17]([NH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:3]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reactant: CCOC(=O)C(F)(F)c1ccc(C)cc1
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(C(F)(F)C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
A solution of tert-butyl [(1S,3S)-3-aminocyclopentyl]carbamate (1.36 g, 6.8 mmol) and ethyl difluoro(4-methylphenyl)acetate (1.45 g, 6.8 mmol) in EtOH (5 mL) was stirred at reflux for 16 h. The solution was cooled to rt. whereupon it solidified. Et2O (6 mL) and hexane (3 mL) were added and the mixture was stirred for 3 h and the solids collected by filtration, rinsing with Et2O (2 mL), and dried to give the title compound (1.051 g) as a solid; MS=313.4 (M+1-isobutylene).
Reaction SMILES: C(NP(CC1C=C2C(=CC=1)NN=C2C1NC2C(C=1)=CC=CC=2)(C1C=CC=CC=1)=O)C.[N+](C1C=CC([O:40][P:41]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)(=[O:61])[O:42][C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[NH:48][N:47]=[C:46]3[C:52]2[NH:53][C:54]3[C:59]([CH:60]=2)=[CH:58][CH:57]=[CH:56][CH:55]=3)=CC=1)([O-])=O.C(NCC)C.N12CCCN=C1CCCCC2>ClCCl>[NH:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:60]=[C:52]1[C:46]1[C:45]2[C:49](=[CH:50][CH:51]=[C:43]([O:42][P:41]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)(=[O:40])[OH:61])[CH:44]=2)[NH:48][N:47]=1
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc3[nH]nc(-c4cc5ccccc5[nH]4)c3c2)c2ccccc2)cc1
Agent: CCNP(=O)(Cc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCNCC
Product: O=P(O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For the purpose of preparing the compound [3-(1H-indol-2-yl)-1H-indazol-5-ylmethyl]phenylphosphinic acid N-ethylamide, a solution of 150 mg of phenyl-phosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester 4-nitrophenyl ester (prepared according to procedure E) and 1.5 ml of diethylamine (2M solution in tetrahydrofuran) in dichloromethane (stabilized with amylene) is stirred at ambient temperature. 44 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added and the medium is stirred overnight at ambient temperature. The solvent is evaporated off in a rotary evaporator and the reaction crude is purified by preparative LC/MS so as to isolate a compound of mass [M+H]+=390, which does not correspond to the expected product. A second fraction of 23 mg of a gray solid identified as phenylphosphonic acid mono-[3-(1H-indol-2-yl)-1H-indazol-5-yl]ester are collected.