Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1)=[O:5].[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[OH:39].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[O:39][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:27])([F:26])[F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1)=[O:5]
Reactant: COc1ccc(O)c(OC)c1
Reactant: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cc(C(F)(F)F)cc(C(F)(F)F)c2C(=O)Nc2ccc(C(=O)O)nc2)c(OC)c1
Temperature: 70 °C
Yield: 22.6 %

Procedure:
Methyl 5-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (60 mg, 0.15 mmol), 2,4-dimethoxyphenol (24.80 mg, 0.16 mmol) and K2CO3 (60.66 mg, 0.44 mmol) were combined in DMF (0.4 mL) and heated at 70° C. Once the reaction was completed (by HPLC), aqueous 5 M NaOH (87.8 μL, 0.44 mmol) was added and the reaction was heated to 50° C. and monitored by HPLC until the reaction was complete. The reaction was cooled to 25° C., filtered and purified by reverse phase HPLC using a gradient of 1-99% ACN in Water and HCl as a modifier to yield 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid (49) (18 mg, 22%). ESI-MS m/z calc. 530.09. found 531.3 (M+1)+; Retention time: 1.54 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.89 (d, J=2.5 Hz, 1H), 8.32 (dd, J=8.6, 2.5 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.90 (s, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.61 (dd, J=8.9, 2.8 Hz, 1H), 3.78 (d, J=14.3 Hz, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:74][C:75]1[CH:84]=[CH:83][C:78]([C:79]([NH:81][CH3:82])=[O:80])=[CH:77][C:76]=1[O:85][CH3:86].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:86][O:85][C:76]1[CH:77]=[C:78]([CH:83]=[CH:84][C:75]=1[NH:74][C:2]1[N:3]=[C:4]([O:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:6]=2[N:7]=1)[C:79]([NH:81][CH3:82])=[O:80]
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(OC3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CCOCC3)c3c(-c4ccncc4)cn(COCC[Si](C)(C)C)c3n2)c(OC)c1
Temperature: 150 °C
Yield: 49.1 %

Procedure:
To a solution of 2-chloro-5-(pyridin-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.1 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (3 equiv). The reaction mixtures were heated, with microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in MeOH) in hexane) to give the title compound (49.1%% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.11 (s, 9H) 0.85-0.93 (m, 2H) 1.68-1.82 (m, 2H) 2.06-2.18 (m, 2H) 2.79 (d, J=4.30 Hz, 3H) 3.51-3.66 (m, 4H) 3.77-3.86 (m, 2H) 3.96 (s, 3H) 5.47-5.55 (m, 1H) 5.56 (s, 2H) 7.50-7.57 (m, 2H) 7.71-7.76 (m, 2H) 7.83 (s, 1H) 7.92 (s, 1H) 8.34 (q, J=4.43 Hz, 1H) 8.52-8.60 (m, 3H); MS (ESI) m/z 605.6 [M+1]+.
Reaction SMILES: [N+](C1C=C(S(O[C@@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)(=O)=O)C=CC=1)([O-])=O.C(#N)CC.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41].C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1
Reactant: Sc1ccccc1Cl
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC#N
Product: COC(=O)[C@@H]1C[C@@H](Sc2ccccc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-(3-nitrophenylsulfonyloxy)pyrrolidine-1,2-dicarboxylate (8.5 g, 19.7 mmol, Eq: 1.00) was combined with propionitrile (82.0 ml) to give a light brown solution. Then 2-chlorobenzenethiol (4.28 g, 3.38 ml, 29.6 mmol, Eq: 1.50) and triethylamine (4.00 g, 5.5 ml, 39.5 mmol, Eq: 2.00) were added dropwise. The reaction was stirred overnight at reflux (100° C.). The reaction was cooled to room temperature, and poured in 50 ml Na2CO3 solution (10%), and extracted with 2×100 ml ethyl acetate. The organic layers were washed with 50 ml HCl 0.1M and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100% to 80% heptane in ethyl acetate). The title compound was obtained as a yellow oil (5.7 g, 77.6%, MS (m/e)=372.1 [M+H+]).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl.O.[S-2].[Na+].[Na+]>CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([C:21]2[NH:1][C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1cccc(N)c1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c12
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
1.5 g (8.3 mmol) of ethyl 2,3-diaminobenzoate and 1.1 ml of concentrated acetic acid were dissolved in 50 ml of methanol. 1.6 g (10.8 mmol) of 4-nitrobenzaldehyde, dissolved in 150 ml of methanol, were then added dropwise over a period of 30 minutes. 2.2 g (10.8 mmol) of copper(II) acetate, dissolved in 100 ml of warm water, were then rapidly added dropwise, and the entire mixture was subsequently refluxed for 20 minutes. The reaction solution was cooled to 50° C. and 3 ml of 32% strength hydrochloric acid were added. This was followed by careful dropwise addition of a solution of 3.1 g of sodium sulfide hydrate in 50 ml of water, and the entire mixture was stirred for another 15 minutes. The reaction solution was poured into ice-water and the resulting precipitate was filtered off with suction. The filtrate was made alkaline using aqueous sodium bicarbonate solution and extracted repeatedly with ethyl acetate. The ethyl acetate phase was separated off, dried and concentrated under reduced pressure. This gave 2.2 g of the intermediate.
Reaction SMILES: [Mg].[I-].[Li+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.[CH:14]1[C:27]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=2[CH:17]=[CH:16][CH:15]=1>O1CCCC1.C(OCC)C>[CH:24]1[C:25]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33]([CH2:10][C:9]5[CH:12]=[CH:13][C:6]([O:5][CH3:4])=[CH:7][CH:8]=5)([OH:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:18]4[C:27]3=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [I-]
Agent: [Li+]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CC2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Reaction time: 18 h
Yield: 68.1 %

Procedure:
Magnesium turnings (0.32 g, 1.32 mmol, 1.3 eq) were stirred in the absence of solvent for 15 min under nitrogen. Diethyl ether (20 mL) and catalytic lithium iodide were added, and the suspension was stirred vigorously for an additional 15 min at which time 4-methoxybenzyl chloride (1.08 mL, 7.0 mmol, 8 eq) was syringed into the reaction flask in portions. The reaction was refluxed for 3 h to assure Grignard formation and recooled to room temperature. 1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (0.30 g, 1.00 mmol) was added dropwise as a tetrahydrofuran solution (25 mL). After stirring for 18 h, the reaction was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (25 mL, eluent: 20% ethyl acetate in hexane) to yield 0.29 g (69%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) 7.23 (m, 2H), 7.13 (m 4H), 6.88 (m, 6H), 4.25 (s, 1H), 3.78 (s, 3H), 3.41 (s, 2H), 2.76 (m, 2H), 2.66 (s, 2H), 2.57 (d, J=1.2 Hz, 2H), 2.52 (m, 2H), 1.67 (m, 2H), 1.47 (m, 2H), 1.57 (s, 1H) MS (CI, CH4) m/z 426 (M+1,100), 454 (M+29,13), 408 (20) The free base was dissolved in methanol and methylene chloride, acidified with ethereal HCl and the salt precipitated with ether dilution. The hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 267°-268° C. (dec).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=2)=[CH:6][C:7]([C@H:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[C:8]([CH:14]=1)[CH2:9][O:10][CH2:11][CH2:12][OH:13].[CH3:63]I>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:38]([O:37][C@H:18]1[C@H:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:20]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:15]([C:7]2[CH:6]=[C:5]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=3)[C:4]([Cl:3])=[CH:14][C:8]=2[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:63])[O:16][C@@H:17]1[CH2:45][O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCCO)cc2Cl)cc1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCCOC)cc2Cl)cc1
Reaction time: 1 h

Procedure:
NaH (2 mg, 0.087 mmol) was added to a solution of 2-(5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyloxy)ethanol (intermediate O-3) (60 mg, 0.073 mmol) in anhydrous THF (10 mL) at 0° C., and stirred for 1 h, then TBAI (2.6 mg, 0.007 mmol) and CH3I (1.5 mg, 0.11 mmol) were added to the reaction mixture at the same temperature and stirred overnight. Then the mixture was washed with water (10 mL×3), then brine, and the organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The residue (intermediate S-1) was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[C:1]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])(=[S:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=S)c1ccccc1)C(C)C
Temperature: 20 °C

Procedure:
To 3.0 g. N-benzoyl-L-valine, methyl ester dissolved in 50 ml benzene was added 0.56 g. phosphorus pentasulfide in one portion at 20° C. The mixture was refluxed for about 4 hours, cooled to about 20° C. and filtered. The resulting oil which was collected was washed with methylene chloride and filtered. The combined filtrates were concentrated under vacuum to yield a yellow oil. Column chromatography with silica gel and a hexane-ethyl acetate solvent system gave 1.89 g. (59%) of a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:5]=2[CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][CH2:8]2)[CH3:2].[CH2:25]([O:29][CH3:30])[CH:26]1[O:28][CH2:27]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[CH2:1]([C:3]1[C:4]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13][C:5]=2[CH:6]=[C:7]2[C:12]=1[N:11]([CH2:27][CH:26]([OH:28])[CH2:25][O:29][CH3:30])[CH2:10][CH2:9][CH2:8]2)[CH3:2]
Reactant: COCC1CO1
Reactant: CCc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1c2c(cc3c1N(CC(O)COC)CCC3)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 140 mg of t-butyl 11-ethyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 1.86 ml of acetonitrile was added 0.12 ml of glycidylmethylether, followed by substitution with argon. In an ice-bath, 9 mg of ytterbium(III) trifluoromethanesulfonate was added thereto, followed by stirring at room temperature for 2 hours, then elevating the temperature to 50° C., and stirring overnight. To the reaction mixture were added EtOAc and aqueous sodium bicarbonate, and the organic layer was washed with water and saturated brine. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 147 mg of t-butyl 11-ethyl-1-(2-hydroxy-3-methoxypropyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1O.BrC1C=CC=CC=1.[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29]C.CCCCCCCCCCCC>[Cu]I.O.C(OCC)C.CN(C=O)C>[C:12]1([CH2:16][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH2:31])[CH:11]=[CH:10][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCN
Reactant: Cc1cccc(C)c1O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Brc1ccccc1
Product: NCCCCCCc1ccccc1
Temperature: 100 °C

Procedure:
Copper (I) iodide (10 mg, 0.05 mmol, 5 mol %), anhydrous fine powder potassium phosphate (425 mg, 2.0 mmol) and 2,6-dimethylphenol (24 mg, 0.2 mmol, 20 mol %) were put into a screw-capped test tube with a Teflon septum. The tube was evacuated and back-filled with argon (3 cycles). Anhydrous DMF (1.0 mL), bromobenzene (105 μL, 1.0 mmol) and n-hexylamine (158 μL, 1.2 mmol) were added by micro-syringe at room temperature. The reaction mixture was heated at 100° C. for 18 hours. The reaction mixture was then allowed to reach room temperature. Diethyl ether (2 mL), water (2 mL) and dodecane (internal standard, 227 μL) were added. The organic layer was analyzed by GC to give 48% GC yield of N-phenylhexylamine.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.[S:25]([CH2:28][C:29]([O:31]C)=O)[C:26]#[N:27].C(O)(=O)C>C(O)C.C(Cl)Cl>[O:31]=[C:29]1[CH2:28][S:25][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:27]1
Reactant: COC(=O)CSC#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C4=NC(=O)CS4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 310 mg), methyl thiocyanatoacetate (121 mg, Bull. Chem. Soc. Jpn. 1972, 45(5), 1507) and glacial acetic acid (55 mg) in absolute ethanol (5 mL) is stirred at reflux under N2 for 4 hrs and then cooled to ambient temperature, diluted with methylene chloride (45 mL), washed with water (2×15 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 45 g), eluting with methanol/methylene chloride (4/96), and those fractions with an Rf =0.47 by TLC (methanol/chloroform, 10/90) are pooled and concentrated to give the title compound, mp 222-224° C. (decomp.).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[C:18]1(CCN)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O>[C:18]1([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: NCCC1=CCCCC1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(1-cyclohexenyl)ethylamine (0.64 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.82 g (55%) of the titled product as yellow needles:
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:10].C(=O)([O-])[O-].[K+].[K+].O.[NH2:24][C:25]1[N:34]=[C:33]([C:35]([N:37]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[N:26]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:24][C:25]1[N:34]=[C:33]([C:35]([N:37]2[CH2:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:45]2)=[O:36])[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:2]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:3]=3[CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH:6]3[CH3:10])[CH:31]=2)[N:26]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: CC1CCCN1Cc1cc(F)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC1CCCN1Cc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 120 °C

Procedure:
136 mg of 1-(2-bromo-4,5-difluorobenzyl)-2-methylpyrrolidine, 100 mg of potassium carbonate, 7 μl of water and 17 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 4 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:16]=2[CH2:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:63][C:64]1[CH:80]=[CH:79][CH:78]=[CH:77][C:65]=1[CH2:66][C:67]1([CH2:74][O:75][CH3:76])[CH2:72][CH2:71][CH2:70][N:69]([NH2:73])[CH2:68]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:63][C:64]1[CH:80]=[CH:79][CH:78]=[CH:77][C:65]=1[CH2:66][C:67]1([CH2:74][O:75][CH3:76])[CH2:72][CH2:71][CH2:70][N:69]([NH:73][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:68]1
Reactant: COCC1(Cc2ccccc2F)CCCN(N)C1
Reactant: Cc1cc(C2=C3CC(C(=O)O)=CC=C3N(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(Cc2ccccc2F)CCCN(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-4H-indazole-5-carboxylic acid (271 mg, 0.546 mmol), HATU (256 mg, 0.67 mmol) and 3-(2-fluorobenzyl)-3-(methoxymethyl)piperidin-1-amine (122 mg, 0.42 mmol) was dissolved in dimethylformamide (2 mL). Diisopropylethylamine (0.366 mL, 2.1 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 h. Upon completion, the reaction was quenched with water (10 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][C:13]=1[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:10])[CH:4]([S:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(Br)C(=O)OC
Reactant: Cc1cc(S)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(Sc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 46 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methyl-benzenethiol (0.340 g, 2.404 mmol) in 20 mL of dichloromethane, was added triethylamine (3.3 mL, 12.020 mmol). After stirring at room temperature under N2 for 46 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine. The organic layer dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes to give the title compound as colorless oil (0.596 g, 92% yield). LC-MS: tR=11.2 min; m/z 271 (M+H)+.