Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]([OH:37])([CH2:33][CH:34](O)[CH3:35])[CH3:32]>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH:34]([CH3:35])[CH2:33][C:31]([OH:37])([CH3:32])[CH3:30])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Reactant: CC(O)CC(C)(C)O
Product: CC(CC(C)(C)O)Oc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 2-Methyl-pentane-2,4-diol by method Y. The product with the molecular weight of 493.63 (C29H36FN3O3) was obtained in this way; MS (ESI): 494 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxyaniline (7.13 g, 46.5 mmol) in acetic acid (30 mL) and water (10 mL) was added acetic anhydride (4.61 mL, 48.9 mmol) at room temperature. The reaction was heated gently on a steam bath then cooled to room temperature. Excess water was added and the title compound 464A was collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:22][O:21][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:1]=[CH:23][NH:6][C:4]2=[O:5]
Reactant: CN(C)C=NC=[N+](C)C
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-5-methoxy4-(3-morpholinopropoxy)benzamide (4.57 g, 12.25 mmol) and Gold's reagent (2.6 g, 15.89 mmol) in dioxane (35 ml) was heated at reflux for 5 hours. Acetic acid (0.55 ml) and sodium acetate (1.0 g) were added to the reaction mixture which was heated for a further 3 hours. The mixture was cooled to ambient temperature and the volatiles removed by evaporation. The residue was adjusted to pH7 with 2 M sodium hydroxide and then purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with methanol (gradient of 0 to 60%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (3.04 g, 78%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][C:15]1[CH:16]=[C:17]2[C:23]([C:24]3[N:29]=[C:28](S(C)=O)[C:27]([F:33])=[CH:26][N:25]=3)=[CH:22][N:21]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]2=[N:19][CH:20]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:33][C:27]1[C:28]([NH:1][CH:2]([C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:29][C:24]([C:23]2[C:17]3[C:18](=[N:19][CH:20]=[C:15]([F:14])[CH:16]=3)[N:21]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:22]=2)=[N:25][CH:26]=1
Reactant: CCOC(=O)CC(N)C(C)(C)CC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)CC
Temperature: 80 °C

Procedure:
To a suspension of ethyl 3-amino-4,4-dimethylhexanoate, 27a, (0.19 g. 1.00 mmol) and 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p- olylsulfonyl)pyrrolo[2,3-b]pyridine, 25a, (0.54 g, 1.20 mmol) in THF (14.4 mL) was added N,N-diisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was refluxed at 80° C. overnight. After removing the solvents under reduced pressure, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexane gradient) to afford 155 mg of the desired product as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.61 (dd, J=9.0, 2.9 Hz, 1H), 8.56 (s, 1H), 8.33 (dd, J=2.7, 1.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.19 (dd, J=10.1, 2.2 Hz, 1H), 4.94 (td, J=10.0, 3.7 Hz, 1H), 3.99 (dt, J=13.7, 6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (dt, J=14.1, 6.9 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H), 1.01-0.94 (m, 8H); 19F NMR (282 MHz, CDCl3) δ −130.39-133.75 (dd, J=9.0, 1.1 Hz, 1F), −158.56 (s, 1F); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.18 minutes (M+H) 572.07.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([F:25])[CH:31]=2)[CH:3]=1)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccc(F)c21
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cncc(F)c3)c2)c2cccc(F)c21
Yield: 25 %

Procedure:
The title compound was synthesized as described for Example 1 in 25% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (0.096 g, 0.25 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.061 g, 0.28 mmol):
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH:9]([CH3:20])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: CI
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28 g of 2,4-dichlorobenzyl 3-pyridyl ketone are dissolved in 800 ml of dimethylformamide and treated portionwise at 0° with 5.5 g of sodium hydride (50% dispersion in oil). After 2 hours at room temperature, 14.9 g of methyl iodide are added and the mixture is stirred at room temperature for an additional 3 hours. Then the mixture is poured into water and extracted with diethyl ether, and the organic phase is washed and dried over anhydrous sodium sulfate and subsequently concentrated. The product is purified by chromatography on silica gel with n-hexane/ethyl acetate (1:2) to yield 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone as an oil.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[CH2:8]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropane carbonyl chloride (4.54 ml) was added dropwise over 5 min to a stirred solution of 4-benzyloxyaniline hydrochloride (11.8 g) and triethylamine (15.33 ml) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solution was diluted with 2N hydrochloric acid (100 ml) and dichloromethane (200 ml). The organic layer was washed with 2N sodium carbonate (100 ml), water (100 ml), 10% brine (50 ml) and dried over anhydrous sodium sulphate. Concentration in vacuo gave a pale brown solid which was washed with diethyl ether (3×50 ml) to afford the title compound (12 g) as a white solid, m.p. 162°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:25]([CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH3:24].C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:37]3[CH2:36][CH2:35][CH:34]([CH2:33][N:25]([CH2:23][CH3:24])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:39][CH2:38]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CCN(Cc1ccncc1)CC1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CCN(Cc1ccncc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and ethyl-piperidin-4-ylmethyl-pyridin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (25%, off-white crystals). HPLC-MS m/z=515.2 (M+1), Rt: 2.77 min.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH2:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12.[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:20][CH3:21]>>[Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH:14][S:28]([C:25]4[CH:26]=[CH:27][C:22]([CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=4)(=[O:30])=[O:29])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12
Reactant: CS(=O)(=O)c1sc(Cl)c2c1-c1nc(N)sc1CC2
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc3c(s2)CCc2c(Cl)sc(S(C)(=O)=O)c2-3)cc1

Procedure:
The title compound was prepared from 6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-amine (61 mg, synthesized according to METHOD I from 1-chloro-3-(methylsulfonyl)-4,5,6,7-tetrahydrobenzo-[c]thiophen-4-one) and 4-n-propylbenzenesulfonyl chloride (46 mg) as described in the synthetic METHOD A to give a white powder (18 mg) with a purity of 90%: MS-ES (pos) m/z 501.2.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]1[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])=[O:15].[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C(#N)C>[CH3:12][O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19]([O:21][Si:39]([C:36]([CH3:38])([CH3:37])[CH3:35])([CH3:41])[CH3:40])[CH2:18][N:17]1[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
29 ml (194 mmol, 1.6 eq) DBU were added to a suspension of 41.4 g (121.4 mmol) (2S,4R)-4-Hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 150 ml acetonitrile at 0° C. To the resulting solution 29.25 g (194 mmol, 1.6 eq) TBDMSCl were added in portions and the reaction was stirred at RT overnight. After concentrating the crude oil was purified by column chromatography with EtOAc/hexane 1:2 on silica gel to give 49.2 g (90%) (2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][Br:21])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)c(Br)c1

Procedure:
A mixture of 1.0 mmol of ethyl 3-bromo-4-methylbenzoate, 1.0 mmol NBS, and 0.02 mmol benzoyl peroxide in 5 mL CCl4 was refluxed for 4 h and then processed by filtration and chromatography to provide ethyl 3-bromo-4-bromomethylbenzoate as an oil.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:17]1[CH:21]=[C:20]([C:22]([O:24]C)=O)[N:19]=[CH:18]1)[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:3].[CH3:26][NH2:27]>O1CCCC1.ClCCl>[CH3:26][NH:27][C:22]([C:20]1[N:19]=[CH:18][N:17]([C@H:4]([CH2:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[C@@H:2]([OH:1])[CH3:3])[CH:21]=1)=[O:24]
Reactant: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)O)cn1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)O)cn1
Temperature: 120 °C

Procedure:
A mixture of methyl 1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylate (obtained in Example 23(7))(25 mg) and methylamine (40% in water; 1 ml) in tetrahydrofuran (3 ml) was heated in a steel sealed tube at 120° C. overnight. The mixture was taken up in dichloromethane, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (30:1) to give a white powder of N-methyl-1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (18.6 mg).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[I:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18].ICC>C1COCC1>[I:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH2:1][CH3:2])[C:17]([OH:19])=[O:18]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1ccccc1I
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Lithium diisopropylamide solution (2.0 M in THF/heptane/ethylbenzene, 3.82 mL, 7.63 mmol) was added to dry THF (10 mL) under an atmosphere of nitrogen and cooled to 0° C. A solution of 2-(2-iodophenyl)acetic acid (500 mg, 1.91 mmol) in dry THF (15 mL) was then added dropwise. This solution was stirred for 40 minutes at 0° C. before the addition of iodoethane (0.92 mL, 11 mmol). The solution was returned to room temperature and stirred for 4 hours. The resulting mixture was quenched with the addition of H2O (10 mL) and then 2 M HCl (20 mL). The aqueous layer was extracted with EtOAc (3×30 mL), the organic layers were combined and washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound I1 as a pale yellow oil (479 mg, 87%); 1H NMR (400 MHz, d6-DMSO) δ 12.49 (s, 1H), 7.88 (dd, J=7.9, 1.2 Hz, 1H), 7.39 (td, J=7.6, 1.2 Hz, 1H), 7.32 (dd, J=7.8, 1.7 Hz, 1H), 7.01 (J m, 1H), 3.77 (t, J=7.5 Hz, 1H), 1.98-1.86 (m, 1H), 1.73-1.60 (m, 1H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.C[N+]1([O-])CCOCC1.ClCCCl>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(O)C2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(=O)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A mixture of alcohol 266 (2.75 g, 10.45 mmol), NMO (5.8 g, 49 mmol) and 4 Å molecular sieves (8.34 g) was suspended in dry DCM (100 mL) and dry 1,2-dichloroethane (100 mL), stirred at room temperature for 45 min, and then cooled to 0° C. for the addition of solid TPAP (0.36 g, 1.03 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h, filtered through Celite®/silica gel using 50% AcOEt in hexanes as an eluent, then concentrated. The residue was purified by flash chromatography (eluent: 30% to 50% AcOEt in hexane) to provide title compound 267 (0.78 g, 29% yield).
Reaction SMILES: [CH3:1][C:2]1([OH:26])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH2:4][CH2:3]1.O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[OH:26][C:2]1([CH3:1])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CCC(C)(O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-ol (Intermediate G) (290 mg, 0.840 mmol) in DCE (10 ml) was added ethyl 7-oxoheptanoate (434 mg, 2.52 mmol) followed by sodium triacetoxyborohydride (534 mg, 2.52 mmol). The reaction mixture was left to stir overnight at room temperature under an atmosphere of nitrogen and then water was added (20 ml). The product was extracted with EtOAc (2×20 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a crude brown oil. Purification of the crude product by C18 reverse phase chromatography eluting with water/acetonitrile afforded the title compound;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]=[CH2:11])=[O:4].[SiH:14]([Cl:17])([Cl:16])[Cl:15]>>[F:1][C:2]([F:12])([F:13])[C:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][Si:14]([Cl:17])([Cl:16])[Cl:15])=[O:4]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOCCOC(=O)C(F)(F)F
Product: O=C(OCCOCCC[Si](Cl)(Cl)Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a heavy-walled tube equipped with a magnetic stir bar, ester (19) (3.97 g, 20.0 mmol, 1.0 equiv.) and H2PtCl6.6H2O (104 mg, 0.20 mmol, 1.0 mol. %) were loaded. The tube was transferred into a glovebox and HSiCl3 (4.10 mL, 40.2 mmol, 2.0 equiv.) was added to the solution. The tube was tightly fastened then removed from the glovebox. The resulting solution was stirred at room temperature for 20 h behind a protecting shield. Purification was achieved by Kugelrohr distillation under high vacuum and provided 5.46 g (82%) of 7-OEG (20) as a colourless oil; bp=115-120° C. (0.09 Torr); 1H NMR (400 MHz, CDCl3) δ 4.52 (m, 2H), 3.76 (m, 2H), 3.56 (t, J=6.2 Hz, 2H), 1.85 (m, 2H), 1.48 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.7 (q, J=42.3 Hz), 114.7 (q, J=284.1 Hz), 71.8, 67.9, 67.0, 22.8, 21.0.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:28]([O:31][C:19]1[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:16][C:15]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)(=[O:30])[CH3:29]
Reactant: COc1ccc(-c2ccc(-c3ccccn3)o2)cc1OC1CCCC1
Reactant: CC(=O)O
Agent: BrBr
Product: COc1ccc(-c2oc(-c3ccccn3)cc2OC(C)=O)cc1OC1CCCC1
Yield: 31 %

Procedure:
A mixture of 2-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(2-pyridyl)furan, (50 mg) from example 2, in acetic acid (2 ml) and bromine were stirred for 15 mins. at room temperature. The reaction mixture was quenched with sodium sulfite extracted with EtOAc dried with sodium sulfate and evaporated in vacuo to afford the unexpected title compound as a beige solid in 31% yield. 1H NMR (300 MHz, CDCl3): δ 1.6 (m, 2H), 1.98-1.8 (m, 6H), 2.3 (s, 3H), 3.88 (s, 3H), 4.82 (m, 1H), 6.91 (dd, 1H), 7.10 (m, 1H), 7.25 (s, 1H), 7.35 (dd, 2H), 7.7 (bs, 2H), 8.58 (d, 1H).
Reaction SMILES: [C:1](OCCCl)(=[O:5])[CH:2]([CH3:4])[OH:3].[C:10]([O:14][CH:15]([CH3:17])[CH3:16])(=[O:13])[CH2:11][OH:12]>C(OCC)C>[C:1]([O:12][CH2:11][C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)OCCCl
Reactant: CC(C)OC(=O)CO
Solvent: CCOCC
Product: CC(C)OC(=O)COC(=O)C(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chloroethyl lactate (1.91 g, 12.5 mmol) and various amounts of isopropyl glycolate (1.48, 2.22 and 2.95 g; 12.5, 18.8 and 25.0 mmol, respectively) in 25 mL of ethyl ether containing 0.125% tert-butylbenzene were added to 1.75 g Lipase P30 powder and the reaction mixtures were agitated on an orbital shaker (175 RPM) at room temperature for 48 hr. After 48 hr, conversion of 2-chloroethyl lactate to the title compound was estimated (by GC, Method A) to be 30, 38 and 44% with 1.0, 1.5 and 2.0 equivalents of isopropyl glycolate, respectively. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C7H10O5Tms (M--CH3) 247.1001, obsd 247.0990. A portion of one of the reactions was partially purified by flash chromatography (ethyl acetate/hexane, 20/80) to give a mixture of 2-chloroethyl lactate and the title compound. The partially purified mixture was separated by flash chromatography (CH2Cl2 /isopropanol, 99/1) to give the title compound: 1H NMR δ 1.27 (d, 6H, J=6.3 Hz), δ 1.49 (d, 3H, J=7.0 Hz), δ 3.28 (d, 1H, J=4.6 Hz), δ 4.42 (m, 1H), δ 4.60 (d, 1H, J=15.8 Hz),δ 4.71 (d, 1H, J=15.8 Hz), δ]5.09 (m, 1H, J=6.3 Hz); 13C NMR 20.3, 21.7, 61.5, 66.9, 69.6, 166.8, 174.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=2)=O)=[CH:7][CH:6]=1)=[O:4].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10]2[S:41][C:13]([C:15]3[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)[nH]2)[nH]1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc(C(=O)OC)[nH]3)s2)[nH]1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A mixture of compound 4 (1.73 g, 5.2 mmol), dry toluene (75 mL), and Lawesson's reagent (1.50 g, 3.7 mmol) was refluxed under an argon atmosphere for 12 hours. The solution was cooled to room temperature and concentrated to one-third its original volume in vacuo. Methanol was added slowly to the toluene until a precipitate appeared. Column chromatography was performed using pure CH2Cl2 (silica gel; 230-400 mesh) as the initial eluant to remove impurities. Conversion to a 50:50 hexanes:EtOAc eluant system yielded 0.86 g (2.6 mmol, 50%) of a yellow solid. 1H-NMR (CDCl3): δ 7.70 (s, 1H), 6.96 (dd, 1H), 6.52 (dd, 1H), 3.93 (s, 3H). 13C-NMR: δ 161.8, 134.0, 132.4, 125.7, 124.0, 117.8, 109.2, 52.2.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:10]1[CH2:9][C@H:8]([NH2:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (intermediate 10, 720 mg, 2.262 mmol) was dissolved in dichloromethane (30 mL) and treated with trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 15 minutes then evaporated to dryness under reduced pressure and further dried under high vacuum. The crude amine salt was used without further purification.