Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>ClCCl.CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([N:21]=[N+:22]=[N-:23])=[O:14])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc2cnccc12
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(=O)c1cccc2cnccc12
Reaction time: 7 h
Yield: 43.7 %

Procedure:
Isoquinoline-5-carboxylic acid monohydrate (5.00 g, 26.2 mmol) was suspended in dichloromethane (200 ml) and N,N-dimethylformamide (5 drops) added. Oxalyl chloride (4.57 ml, 52 mmol) was then added and the reaction stirred for 7 h. The solvent and excess oxalyl chloride was then evaporated and the residue taken up in dichloromethane (200 ml). A solution of sodium azide (2.1 g, 32.3 mmol) and tetra-n-butylammonium bromide (850 mg) in water (50 ml) was then added in one portion and the mixture stirred for 20 min. The layers were separated and the aqueous phase extracted with more dichloromethane (100 ml). The combined organic phases were evaporated and the residue purified by flash column chromatography (eluant ethyl acetate-dichloromethane (1:4)) to give the title compound as a yellow solid (2.27 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH:9]2[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH2:10]2)[S:4][N:3]=1.S([O-])(=O)(=O)C.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=1>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([C:35]([F:36])([F:38])[F:37])[CH:23]=2)=[C:5]([C:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1C(F)(F)F
Reactant: CC1=CCC(c2snc(Cl)c2CO)CC1
Agent: CS(=O)(=O)[O-]
Product: CC1CC=C(c2snc(Cl)c2COc2ccc(CCC(=O)O)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 127, following Steps 6-7, by conversion of (3-chloro-5-(4-methylcyclohex-3-en-1-yl)isothiazol-4-yl)methanol to the corresponding mesylate and coupling with ethyl 3-(4-hydroxy-2-trifluoromethylphenyl)propanoate. Upon hydrolysis, compound 276 was afforded as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.24-7.30 (m, 1H), 7.10-7.23 (m, 1H), 7.06-7.10 (m, 1H), 6.13 (bs, 1H), 4.96 (s, 2H), 3.11 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.42-2.65 (m, 3H), 1.71-1.87 (m, 3H), 1.26-1.42 (m, 1H), 0.99 (d, J=6.3 Hz, 3H). 19F NMR (300 MHz, CD3OD) δ: −60.07. Mass spectrum (ESI, m/z): Calcd. for C21H21ClF3NO3S, 458.1 (M−H). found 458.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=O.N1CCCC1>C(O)C>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1
Temperature: 90 °C

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol), 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (29 mg, 0.23 mmol) and pyrrolidine (0.006 mL) in ethanol (0.5 mL) was refluxed for 2 hours at 90° C. The reaction was cooled and the precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:6])[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN(C)CCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A suspension of 2-methoxy-N-methylethanamine (266) (20.0 g, 224 mmol), N-(3-bromopropyl)phthalimide (50.1 g, 187 mmol) and K2CO3 (31.0 g, 224 mmol) in DMF (200 mL) was stirred at 100° C. for 3 h. The solution was cooled and the solvent evaporated to give phthalimide 298 (51.7 g, 100%) as a colourless oil, which was used without further purification: 1H NMR δ 7.82-7.86 (m, 2H, Harom), 7.68-7.73 (m, 2H, Harom), 3.73 (t, J=7.2 Hz, 2H, CH2N), 3.42-3.46 (m, 2H, CH2O), 3.32 (s, 3H, OCH3), 2.53-2.56 (m, 2H, CH2N), 2.44-2.49 (m, 2H, CH2N), 2.25 (s, 3H, NCH3), 1.82-1.90 (m, 2H, CH2); HRMS (Cl+) calcd for C15H21N2O3 (MH+) m/z 277.1552, found 277.1557.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12].C(N(CC)CC)C>C1C=CC=CC=1>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:1][C:15](=[O:16])[NH:14][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)N=C=O
Reactant: O=C(CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)NC(=O)OCC(=O)c1ccccc1
Yield: 36.9 %

Procedure:
A mixture of α-hydroxyacetophenone (7.0 g, 51.4 mmol), isopropyl isocyanate (10.1 ml, 102.8 mmol) and triethylamine (7.2 ml, 51.4 mmol) in 150 ml of benzene was refluxed under nitrogen overnight. The reaction was diluted with benzene, extracted with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to 9.741 g of a brown solid. Recrystallization of the solid from isopropyl alcohol gave isopropyl-carbamic acid 2-oxo-2-phenyl-ethyl ester (4.2 g, 38%) as yellow solid, mp 108-110° C.
Reaction SMILES: [C:1]([O-:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C(O)CCCCCCC.C([Li])CCC.Br[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Br:34])=[CH:29][N:28]=1>CCCCCC.O1CCCC1>[Br:34][C:30]1[CH:31]=[C:32]([Cl:33])[C:27]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:28][CH:29]=1
Reactant: Clc1cc(Br)cnc1Br
Reactant: CCCCCCCC(=O)[O-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCCCO
Solvent: CCCCCC
Product: CCCCCCCCOc1ncc(Br)cc1Cl

Procedure:
Lithium octanoate (prepared in advance from 13.02 g (100.00 mmol) of 1-octanol and 69 ml (110.00 mmol) of a 1.6 molar n-butyllithium solution in n-hexane in 40 ml of tetrahydrofuran at 0° C.) and 27.13 g (100.00 mmol) of 2,5-dibromo-3-chloropyridine are refluxed for 7 hours in 40 ml of tetrahydrofuran. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, the ether phase is washed twice with aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is freed from the solvent. Chromatographic purification (silica gel/hexane:ethyl acetate 9:1) gives 18.19 g (59.80 mmol) of 5-bromo-3-chloro-2-octyloxypyridine. ##STR21##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:17])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Cl)c(O)c2c1C
Temperature: -10 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.5 g, 2.27 mmol) was added 5 mL of carbon tetrachloride, and the mixture was cooled with an ethanol/ice bath while 1 equivalent of N-chlorosuccinimide was added in small poroom temperatureions. After stirring at −10° C. for 3 h, the reaction mixture was filtered and the filtrate was loaded onto a silica column and chromatographed to give 259 mg (48% yield) of 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([CH3:16])([CH3:15])[O:11][CH2:12][C:13]#[CH:14])([CH3:9])([CH3:8])[CH3:7].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Si:10]([O:11][CH2:12][C:13]#[C:14][C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
To 50 mL of a 1.6M solution of n-BuLi (0.080 mol, 1 equ) in hexanes was added dropwise tert-butyldimethyl(prop-2-ynyloxy)silane (13.57 g; 0.080 mol; 1 equ) with dry ice acetone cooling. After addition the dry ice acetone bath was replaced by an ice acetone bath. When the mixture became difficult to stir toluene (25 mL) was added. The mixture became clear and was stirred at −10° C. for 15 min. To the resulting slightly yellow solution was added ethyl 2,2,2-trifluoroacetate (11.3 g; 0.080 mol; 1 equ) with cooling in a dry ice acetone bath (ca <−40° C.). After addition the dry ice acetone bath was replaced by an ice acetone bath and the mixture was stirred with thawing to room temperature for 18 h. The reaction mixture was poured onto ice mixed with 10% aqueous citric acid. The phases were separated and the organic phase was washed with 10% aqueous sodium bicarbonate and brine and purified by filtration over ca 350 g silica gel using heptane:dichloromethane=1:1 as eluent. The product fractions (dichloromethane:heptane 1:1; r.f.:0.3 KMnO4 staining) were pooled and evaporated to yield the title compound as an orange yellow oil (16.0 g, 75.4% Th), MS 266.277 (M.)+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][C:5]3[C:10]([CH:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.C1C2C(=CC=CC=2)C=C1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:1][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: C1CCNC1
Agent: C1=Cc2ccccc2C1
Product: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Reaction time: 0.25 h

Procedure:
1,2-Epoxy-2,3-dihydro-1-H indene, prepared from indene (34.2 g) according to the procedure of M. Imuta and H. Ziffer, J. Org. Chem., 44, 1351 (1979), was treated immediately with pyrrolidine (50 ml). The exothermic reaction mixture was set aside for 15 minutes and then evaporated to remove the excess pyrrolidine under reduced pressure. The residue was distilled under vacuum to yield trans-2,3-dihydro-2-hydroxy-1-(pyrrolidin-1-yl)-1H-indene (10.2 g), b.p. 148°-150°/0.25 torr.
Reaction SMILES: [C:1]1(=O)[CH:6]2[C:7]3[C:12]([C:13](=O)[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.B.O.Cl>O1CCCC1>[CH2:1]1[CH:6]2[C:7]3[C:12]([CH2:13][N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C1NCCN2C(=O)c3ccccc3C12
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CN1CCNCC21
Reaction time: 18 h
Yield: 85.2 %

Procedure:
3,4-Dihydropyrazino[2,1-a]isoindole-1,6(2H,10bH)-dione (described in Example 6, 14 g, 0.0674 mol) is added portionwise to 700 ml of 1 M borane in tetrahydrofuran over a 0.5 hr period and then refluxed with stirring for 18 hr. The reaction is cooled, water is added dropwise until the hydrolysis is complete and then 140 ml of 6 N hydrochloric acid is added cautiously. Most of the tetrahydrofuran is distilled off until the distillation temperature reaches 90° C. Then 6 N sodium hydroxide (140 ml) is added and the solution is extracted with chloroform. The chloroform extract is washed with water, dried and evaporated to give the title compound (10 g), nmr (CDCl3) δ 2.63(s), 2.6-4.3(m) and 7.3(m). The title compound is treated with a solution of hydrogen bromide in diethyl ether to give a solid. The solid is crystallized from ethanol to obtain the hydrobromide salt of the title compound, mp 155°-160° C. The title compound (8.9 g) is dissolved in a solution of ethanol containing maleic acid (6.45 g), charcoal is added and the mixture is filtered. The filtrate is evaporated and the residue is crystallized from ethanol-diethyl ether to obtain the maleate salt of the title compound, mp 133°-136° C., Anal. Calc'd. for C11H14N2.C4H4O4 : C, 62.06%, H, 6.25% N, 9.65% and Found: C, 62.00% H, 6.29% N, 9.70%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11](/[CH:13]=[C:14]3/[CH2:15][C:16](=[CH:20][CH:21]=[CH:22]/3)[C:17]([OH:19])=[O:18])[C:10](=[O:23])[C:9]=2[CH:24]=1)=[O:4]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])[C:10](=[O:23])[C:9]=2[CH:24]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)C(/C=C1\C=CC=C(C(=O)O)C1)O2
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)C(=O)C(Cc1cccc(C(=O)O)c1)O2

Procedure:
The product from (a) (1 g) was suspended in glacial acetic acid (100 ml) and hydrogenated at 60 p.s.i. in the presence of 10% palladium on carbon (100 mg). After 1 hour the catalyst was filtered off and the colourless filtrate evaporated in vacuo to give a light straw coloured oil which crystallised on standing. Recrystallisation from ethyl acetate/petrol gave the required product as off-white crystals, m.p. 140°-143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@H:7]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8][C@@H:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:40]1([CH3:64])[CH:45]=[CH:44][C:43]([S:46]([O:49][CH2:50][CH2:51][CH2:52]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1>CN(C)C=O>[C:14]([O:13][C:11]([NH:10][C@H:9]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:8][C@H:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:52][CH2:51][CH2:50][O:49][S:46]([C:43]2[CH:42]=[CH:41][C:40]([CH3:64])=[CH:45][CH:44]=2)(=[O:47])=[O:48])=[CH:33][CH:32]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(N)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 100 °C

Procedure:
To 230 mg (0.5 mmol) of di-tert-butyl (4S)-4-(4-aminobenzyl)-N-(tert-butoxycarbonyl)-L-glutamate in 12 mL N,N-dimethylformamide were added 138 mg (1.0 mmol) of potassium carbonate and 385 mg (1.0 mmol) of 1,3-propanediol di-p-toluenesulfonate (Aldrich) and the resulting suspension was heated for 1 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in dichloromethane. The crude product obtained in this manner was chromatographed on a Biotage® SNAP cartridge KP-NH using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:12][C:13]#[N:14])[C:5]=2[N:6]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C=O>[CH3:11][C:9]1[CH:8]=[C:7]([S:12][C:13]#[N:14])[C:5]2[N:6]=[C:2]([NH:1][C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=3)=[O:26])[S:3][C:4]=2[CH:10]=1
Reactant: Cc1cc(SC#N)c2nc(N)sc2c1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Cc1cc(SC#N)c2nc(NC(=O)Nc3ccc([N+](=O)[O-])cc3)sc2c1
Reaction time: 5 h

Procedure:
A mixture of 2-amino-6-methyl-4-thiocyanatobenzothiazole (35 g., 0.16 mole) in dimethylformamide (250ml.) was treated slowly with p-nitrophenyl isocyanate (27 g., 0.16 mole). The reaction was then heated under stirring on the steam bath for 5 hours. The mixture was then filtered hot. The solution was chilled in an ice bath and filtered. The product was combined with the solid initially filtered to give 40 g. (65%) of off-white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([Li])CCC>C1COCC1>[C:1]1([CH2:7][C:8]([N:33]2[C@@H:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][O:35][C:34]2=[O:37])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 10 gm of phenylacetic acid (73 mmol) and 12.2 mL of triethylamine (87.6 mmol) in 200 mL of THF was cooled to −78° C. To this solution was added 9.8 mL of trimethylacetyl chloride (80 mmol) and the reaction was warmed to 0° C. and stirred for 1 hr. This solution was recooled to −78° C. (Solution #1) Meanwhile, to a solution of 14.2 gm of (S)-(−)-4-benzyl-2-oxazolidinone in 200 mL of THF at −78° C., was added 50 mL of a 1.6M solution of n-butyl lithium in THF (80 mmol)over 20 min. (Solution #2) After stirring for 20 min., this solution (#2) was slowly cannulated into the solution (#1) containing the mixed anhydride at −78° C. This reaction mixture was allowed to warm to room temperature and stirred for 2 hr. The reaction was quenched with a solution of saturated NH4Cl and extracted with ethyl acetate. The combined organic fractions were washed with water, sat. NaHCO3 solution, sat. NaCl solution, dried over MgSO4, filtered and concentrated. The crude product was purified by chromatograpy (silica, hexanes:ethyl; acetate=4:1) to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[CH2:26](B1C2CCCC1CCC2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O>[CH2:26]([C:2]1[C:3]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Br)cn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Cc3ccccc3)cn2)n1
Temperature: 80 °C
Yield: 9.7 %

Procedure:
A vial was charged with 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (0.0199 g, 0.0242 mmol), N-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine (0.100 g, 0.242 mmol), 9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.45 ml, 0.726 mmol), cesium carbonate (0.237 g, 0.726 mmol), DMF (5 mL), and water (1.5 mL). The reaction mixture was heated at 80° C. for three days. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The crude material was purified by reverse phase column chromatography to give the title compound (0.010 g, 9.25% yield) as a white solid. 1H NMR (CDCl3) δ 8.85 (dd, 1H), 8.17 (s, 1H), 7.96 (d, 1H), 7.60 (t, 1H), 7.56 (d, 1H), 7.25 (m, 3H), 7.22 (s, 1H), 7.19 (m, 1H), 7.15 (dd, 1H), 7.04 (d, 1H), 6.05 (s, 1H), 5.75 (s, 1H), 4.04 (s, 2H), 1-69 (s, 3H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[I-:27].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[OH:1][C:3]1([CH2:2][I:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: [I-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CI)CC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (10.0 mmol) and sodium iodide (11.0 mmol) in presence of catalytic p-toluene sulfonic acid in dimethyl formamide at a temperature 50-60° C. for 12 hours to provide crude (S)-N-{3-[4-(4-hydroxy-4-iodomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide which was purified by silica gel column chromatography and used further.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.C12NC(CC1)CC2>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([N:36]3[CH:43]4[CH2:44][CH2:39][CH:40]3[CH2:41][CH2:42]4)=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Reactant: On1nnc2ccccc21
Agent: C1CC2CCC1N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.9 %

Procedure:
To a stirred solution of (S)-2-[3-(2-tert-butoxycarbonylamino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (2.5 g in 25 mL dry methylene chloride) at 0° C. was added 1-hydroxybenzotriazole (1.0 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.24 g) and the reagents allowed to mix for 1 hour. At this time a solution of 7-aza-bicyclo[2.2.1]heptane hydrochloride (1.44 g) was added followed by 1.5 mL triethylamine and the reaction stirred at room temperature. After 21 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 1:1) to give the title compound (2.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:5]2.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:5]2
Reactant: BrCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.2 %

Procedure:
A mixture of the phenol from step B (13.62 g, 55.14 mmol) and 2-bromomethylquinoline (12.85 g, 1.05 mol eq.) and anhydrous K2CO3 (15.22 g, 2 mol. eq.) in DMF (40 ml) was stirred at RT for 48 hours. The mixture was then poured onto ice/water and after all the ice had melted, the brown solid was collected and air-dried. The dried material was passed through a plug of silica (using EtOAc/hexane (1:3) as eluent) to remove the color; yield: 19 g, 88%. Recrystallization from EtOH afforded 14.17g of pure title compound, m.p. 131°-132° C.