Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[CH3:36][C:37]1[CH:54]=[CH:53][C:40]([C:41]([NH:43][C:44]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH2:46][CH2:45]2)=[O:42])=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:18]([N:13]([C:12]1[C:7]([C:38]2[CH:39]=[C:40]([C:41](=[O:42])[NH:43][C:44]3([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:45][CH2:46]3)[CH:53]=[CH:54][C:37]=2[CH3:36])=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cc(C(=O)NC2(c3ccccn3)CC2)ccc1C)S(C)(=O)=O
Temperature: 90 °C

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.07 g, 0.13 mmol, 1 eq), 4-methyl-N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.054 g, 0.14 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0045 g, 0.0039 mmol, 0.03 eq) and cesium carbonate (0.12 g, 0.39 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). Nitrogen gas was passed through the solution and the reaction was heated at 90° C. for 14 h. The solution was filtered through celite. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%). 1HNMR (400 MHz, CD3OD): δ 1.12 (broad s, 3H), 1.35 (s, 2H), 1.66 (s, 2H), 2.34 (s, 3H), 2.85 (s, 3H), 3.00-3.32 (br, 3H), 3.51 (br, 2H), 7.13 (m, 1H), 7.24 (m, 2H), 7.46 (m, 2H), 7.68 (m, 1H), 7.97 (m, 4H), 8.0 (s, 1H), 8.41-8.42 (d, J=4 Hz, 1H), 8.92 (s, 1H). LCMS: (ES+) m/z=641.2 (M+H) Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min; RT min: 1.796; Wavelength: 220 nm. HPLC Method: SUNFIRE C18 (4.6×150) mm, 3.5 micron; Buffer: 0.05% TFA in water pH 2.5; Mobile Phase A: Buffer: MeCN (95:5); Mobile Phase B: MeCN: Buffer (95:5); FLOW: 1 ml/min; Wavelength: 254 nm, RT min: 8.675; Purity: 96.6%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[Cl:45])=[O:35])[CH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)=[O:19])=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:12])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[Cl:45])=[O:35])[CH2:16][CH2:17][C:18](=[O:19])[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1nc2ccccc2s1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of (S)-tert-butyl 4-(5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (713 mg, 1.05 mmol) in DCM (5 mL) was added TFA (1 mL) and allowed to stir for 30 min. The reaction mixture was concentrated, and the residue purified by RP-HPLC (20-100% ACN in H2O) and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl benzo[d]thiazol-2-ylcarbamate as an off-white solid (430 mg, 71%). LRMS (M+H+)=577.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[C:18]([O:24][CH2:25][CH3:26])=[C:17]([O:27][CH2:28][CH3:29])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:39]1([C:45]2([C:51]([NH2:53])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:48]3[CH2:47][CH2:46][C:45]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:51]([NH2:53])=[O:52])[CH2:50][CH2:49]3)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[C:18]([O:24][CH2:25][CH3:26])=[C:17]([O:27][CH2:28][CH3:29])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CCOc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OCC)c1OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OCC)c1OCC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate ((1 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.29 g, 1.2 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane and then 6% methanol/dichloromethane to give the title compound: Rf =0.36 (silica gel, 10% methanol in dichloromethane). Exact mass (FAB+): calculated for C37H46Cl2N3O5 calculated 682.2815. Found 682.2799.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)([CH3:28])[CH3:27])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:22]([O:24][C:25](=[O:37])[C:26]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:2][C:3]2[C:4]([CH:19]3[CH2:21][CH2:20]3)=[N:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[N:7][CH:8]=2)=[CH:34][CH:35]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 418 mg (1.34 mmol) 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine and 300 mg (1.34 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] in 5 ml DMF was treated with 523 mg (1.61 mmol) cesium carbonate. The reaction mixture was stirred 4 h at RT and then it was taken up in ether and washed with 1N HCl and water. The ether layers were concentrated under reduced pressure and the crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 giving 550 mg of pure 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][OH:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.O.CCOC(C)=O>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([CH2:29][OH:30])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 74.9 %

Procedure:
A solution of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl) pyrimidin-2-yl) thiophene-2-sulfonamide (89 mg, 0.17 mmol, 1.0 eq) and BCl3 (1.0 ml, 1.0 mmol, 6.0 equiv.) in CH2Cl2 (5 mL) was stirred for 1 h at 0° C. After addition od water and extraction with EtOAc (3×50 ml), the combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to produce 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 171) (50.0 mg, 74.8%) as white solid. LC-MS (m/z)=393.0 [M+H]+; 1H 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.97-0.99 (m, 2H), 1.92-1.96 (m, 1H), 4.56 (d, J=5.2 Hz, 2H), 5.61 (t, J=5.2 Hz, 1H), 6.53 (d, J=10.4 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.78 (s, 3H), 8.24 (s, 1H), 8.95 (s, 1H), 12.16 (s, 1H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])([CH3:16])[CH3:15]>C(O)C>[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][P:27]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:28])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:15])[CH3:16]
Reactant: CCOP(=O)(CCNCCCCNC(=O)OC(C)(C)C)OCC
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N(CCCCNC(=O)OC(C)(C)C)CCP(=O)(OCC)OCC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.8 mL, 39 mmol) in absolute ethanol (200 mL) prepared under nitrogen, was added a solution of [4-[[2-(diethoxyphosphinyl)ethyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester (13.7 g, 39 mmol) in ethanol (75 mL) over 1.75 hour. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in chloroform (150 mL), preadsorbed onto silica gel, and purified by flash chromatography (9 cm diameter, elution with 2.5% methanol in dichloromethane) to yield [4-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]butyl]carbamic acid 1,1-dimethylethyl ester as a yellow viscous oil (16.8 g, 90%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:9][C:10]1[C:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:32]3[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=3)[CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nc(CC2CCNCC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(CC2CCN(c3ccc(Br)cn3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 22 h
Yield: 54.7 %

Procedure:
tert-Butyl 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylate hydrochloride (6.5 g, 15 mmol), 2,5-dibromopyridine (5.3 g, 7.5 mmol) and potassium carbonate (6.2 g, 45 mmol) were suspended in N,N-dimethylformamide (150 mL), followed by stirring at 100° C. for 22 hours. The reaction solution was concentrated under reduced pressure, followed by addition of ethyl acetate, and subsequently the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.3 g, 4.1 mmol) as a colorless oil (yield 27%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:31]=2[N:32]=[CH:33][N:34]=1)[C@@H:15]1[O:30][C@H:19]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[C:1]([NH:9][C:10]1[N:34]=[CH:33][N:32]=[C:31]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:15]1[O:30][C@H:19]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 920 mg (2 mmol) of N6,5'-O-dibenzoyl-2'-deoxyadenosine (was prepared by the method described by Nishino et al., Nucleosides & Nucleotides 1986, 5, 159) in 30 ml of abs. dichloromethane (contains 2 ml of pyridine) is cooled to -30° C., and 5 ml of a solution of trifluoromethanesulfonic anhydride in dichloromethane (10% by vol.) are slowly added dropwise. After removal of the cooling bath, the solution is left to warm and 1 ml of water is added. After 3 h, a further 5 ml of water are added and the organic phase is washed. After removal of the solvent, the remaining residue is dissolved in 50 ml of methanol, and 100 mg of sodium bicarbonate are added. The mixture is stirred for a further 2 h at RT, neutralized with 10% strength acetic acid, the solvent is removed by distillation, and purification is carried out by flash chromatography on silica gel (chloroform:methanol 97:3). Yield 710 mg (1.48 mmol) 75%. Rf chloroform:methanol 97:3=0.49. MS=459.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[CH:28]1([CH:34]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCCCC1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCN(CC2CCCCC2)C1

Procedure:
To a solution of 600 mg of 3-(benzyloxycarbonyl)amino-N-{((3S)-3-piperidyl)methyl}propanamide in 3 ml of methanol, a solution of 150 mg of sodium cyanoborohydride and 160 mg of zinc chloride in 8.1 ml of methanol, and 0.30 ml of cyclohexanecarbaldehyde were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate and successively washed with saturated aqueous sodium bicarbonate solution and saturated saline, followed by drying over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 775 mg of the title compound was obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9](OCC)=O)=[C:6]([OH:14])[C:5]=1[OH:15].CBr.Cl>O>[CH3:3][CH:4]1[C:5](=[O:15])[C:6]([OH:14])=[C:7]([CH3:9])[O:8]1
Reactant: CCOC(=O)c1oc(C)c(O)c1O
Agent: CBr
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1=C(O)C(=O)C(C)O1
Temperature: 25 °C
Reaction time: 40 h
Yield: 81.4 %

Procedure:
A solution of 48 g of sodium hydroxide and 37.2 g of ethyl 5-methyl-3,4-dihydroxy-2-furoate of 98.4% purity in 225 ml of water was allowed to stand at room temperature for 40 hours. The mixture was diluted with 200 g of water and 22.8 g of gaseous methyl bromide was added with stirring over a period of one hour at room temperature followed by an additional stirring period of two hours. The pH of the solution was adjusted to 5 by the addition of concentrated hydrochloric acid solution. Extraction with methyl t-butyl ether yielded 21.5 9 of 2,5-dimethyl-4-hydroxy-3[2H] furanone of 95.3% purity (molar yield 81.4%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25]1([C:57]3[C:48](=[CH:49][C:50]4[O:55][CH2:54][CH2:53][O:52][C:51]=4[CH:56]=3)[O:47][CH2:46]1)[C:26](=[O:45])[N:27]2[CH:32](C1C=CC=CC=1)C1C=CC=CC=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[C:25]2([C:57]4[C:48](=[CH:49][C:50]5[O:55][CH2:54][CH2:53][O:52][C:51]=5[CH:56]=4)[O:47][CH2:46]2)[C:26](=[O:45])[N:27]3[CH3:32])=[CH:2]1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: OB(O)c1ccoc1
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3ccoc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 3-furanboronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: mp 178-180° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 2H), 7.00 (d, J=7.9 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 6.04-6.01 (m, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (d, J=9.0 Hz, 1H), 4.23-4.09 (m, 4H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.5, 144.7, 144.3, 142.8, 140.5, 137.9, 130.8, 129.1, 128.1, 125.2, 122.6, 122.5, 111.2, 111.1, 107.4, 99.7, 76.7, 64.6, 64.0, 58.3, 26.8; MS (ES+) m/z 375.9 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]([NH:25]C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:15][CH:14]=1)(C)(C)C.Cl>CCOCC>[NH2:25][C@@H:9]([CH2:8][NH2:7])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](CCCc1ccc(OC[C@H](O)CO)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: NC[C@H](N)CCCc1ccc(OC[C@H](O)CO)cc1

Procedure:
{(R)-2-tert-Butoxycarbonylamino-5-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-pentyl}-carbamic acid tert-butyl ester (94 mg, 0.201 mmol) is stirred with a solution of 1 M HCl in Et2O (3 ml) for 18 hours and then loaded onto a 1 g SCX-2 cartridge washed with MeOH (30 ml), followed by 7M NH3 in MeOH (30 ml). The NH3 fraction is concentrated in vacuo to give the title compound, (R)-3-[4-((R)-4,5-Diamino-pentyl)-phenoxy]-propane-1,2-diol Intermediate H(R)-3-[4-((R)-4,5-Diamino-pentyl)-phenoxy]-propane-1,2-diol; [M+H]+ 269
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]([CH2:18][O:19][CH2:20][C:21]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:15]3[C:11](=[CH:12][N:13]([CH3:40])[N:14]=3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>FC(F)(F)C(O)=O>[CH3:40][N:13]1[CH:12]=[C:11]2[C:15]([C:16]([CH2:18][O:19][CH2:20][C:21]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[CH:17][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[CH:10]2)=[N:14]1
Reactant: Cn1cc2cc(-c3ccc(C#N)cc3)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc2cc(-c3ccc(C#N)cc3)cc(COCC3(c4ccccc4)CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-2-methyl-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (29 mg, 0.054 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 4 mL) and stirred at room temperature for 45 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol to give 20 mg (85%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.71 (m, 3H), 7.61 (m, 2H), 7.41 (m, 2H), 7.30 (m, 3H), 7.18 (m, 1H), 4.89 (s, 2H), 4.21 (s, 3H), 3.60 (s, 2H), 2.90 (m, 2H), 2.75 (m, 2H), 2.19 (m, 2H), 1.95 (m, 2H), 1.92 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 147.0, 146.4, 144.6, 132.9, 132.6, 128.8, 128.3, 127.8, 127.4, 126.0, 124.8, 122.5, 122.3, 119.3, 117.5, 110.3, 80.2, 68.9, 42.8, 42.0, 40.7, 33.7. Mass spec.: 437.17 (MH)+. Accurate mass spec.: m/z 437.2339 [MH]+, Δ=0.5 ppm.
Reaction SMILES: Cl[SiH](C1C=CC=CC=1)C1C=CC=CC=1.[CH2:15]([N:22]1[CH2:36][CH:25]2[C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[CH:30][C:31]=3[CH:32](O)[CH:24]2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[CH2:15]([N:22]1[CH2:23][CH:24]2[CH2:32][C:31]3[CH:30]=[CH:29][C:28]([O:34][CH3:35])=[CH:27][C:26]=3[CH:25]2[CH2:36]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2O
Agent: Cl[SiH](c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
InCl3 (0.38 g, 1.7 mmol) and chlorodiphenylsilane (1.3 mL, 6.8 mmol) were added to a solution of 2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]inden-8-ol (3.4 mmol) in DCE (17 mL), and stirred overnight at 60° C. The reaction mixture was washed with H2O, a saturated aqueous NaHCO3 solution and brine. The organic extracts were dried over MgSO4 and concentrated. The crude product was obtained without further purification. MS calculated for C19H21NO+H: 280, observed: 280.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:14][C:15]([O:17]C)=O)[NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].P([O-])([O-])([O-])=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][C:15](=[O:17])[N:12]([CH3:13])[C:10](=[O:11])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)NN(CC(=O)OC)c1cccc(Cl)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CN(c2cccc(Cl)c2)NC1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57 %

Procedure:
Methyl [1-(3-chlorophenyl)-2-[(methylamino)carbonyl]hydrazino]acetate (700 mg) was dissolved in methanol (25 ml) under nitrogen. Solid sodium methoxide (350 mg) was added to the solution which was then stirred at room temperature for 40 min. The reaction was poured into pH 6.5 phosphate buffer solution (100 ml) and extracted with ethyl acetate (3×70 ml). The combined, dried organic extracts were concentrated in vacuo to give a solid which was triturated with ether (2×20 ml) to give the title compound (352 mg), m.p. 178°-180°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26](CC[Si](C)(C)C)[C:25](=[O:36])[CH2:24]1)C1C=CC=CC=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]2[CH2:16][CH2:15][C:13]2[CH:12]=[CH:11][C:10]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:36])[CH2:24]3)=[C:9]([OH:8])[CH:14]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(CCC3CCCCN3S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-(E)-2-piperidin-2-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 92, step A) and benzenesulfonyl chloride analogous to Example 193: LC retention time=1.28 min (Method A); (M−1)−=478.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([CH2:10]O)[CH:2]=1.P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:13][CH2:10][C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: OCc1cnn2ccccc12
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1cnn2ccccc12

Procedure:
To the solution of pyrazolo[1,5-a]pyridin-3-ylmethanol (2) (50 mg, 0.338 mmol) in DCM (2 mL) was added PBr3 (36.58 mg, 0.135 mmol) at room temperature for 30 min. The reaction solution was used in the next step.