Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:4]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C(C)C)c(O)c(C(C)C)c1

Procedure:
4-(2-Methoxycarbonylvinyl)-2,6-diisopropylphenol (Example 1, 350 mg) was dissolved in a solution of ethyl acetate (10 mL) and methanol (10 mL) and hydrogenated at 35 psi over palladium on carbon (Pd/C) for 24 hours. The resulting mixture was filtered and the filtrate was concentrated to provide the title compound; 1H-NMR (CDCl3) δ=1.27 (d, 12H, CH(CH2)2), 2.60 (t, 2H, CH2), 2.87 (t, 2H, CH2), 3.13 (m, 2H, CH(CH3)2), 3.68(S, 3H, OCH3), 6.87 (S, 2H, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:34]4[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: CCN1CCNCC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: CCN1CCN(C(=O)c2ccc(CCc3cnc4c(N)nc5cc(C)ccc5c4c3)c(C)c2)CC1

Procedure:
(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)methanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and 1-ethylpiperazine following the procedures described for Example 117. 1H NMR (Methanol-d4): δ 8.59 (s, 1H), 8.37 (s, 1H), 8.06 (d, 1H), 7.32 (s, 1H), 7.00-7.12 (m, 4H), 3.67 (br, 2H), 3.06-3.13 (m, 4H), 2.45 (br, 4H), 2.37 (q, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.19 (br, 2H), 1.04 (t, 3H), LRMS [M+H]=468.3
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1N1CCC[C@H](O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (S)-3-hydroxypiperidine and triethylamine in DMF yielding (S)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[C@@H:4]([CH2:5][CH2:6][NH:7]2)[N:3]1[S:9]([OH:12])(=[O:11])=[O:10].CC#N.C([O-])(O)=O.[Na+].[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](ON2C(=O)CCC2=O)=[O:36])=[CH:30][CH:29]=1)=[O:26]>O>[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C@@H:4]3[C@H:8]2[C:2](=[O:1])[N:3]3[S:9]([OH:12])(=[O:11])=[O:10])=[O:36])=[CH:30][CH:29]=1)=[O:26]
Reactant: O=C1[C@H]2NCC[C@H]2N1S(=O)(=O)O
Reactant: NCCNC(=O)Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCCNC(=O)Nc1ccc(NC(=O)N2CC[C@@H]3[C@H]2C(=O)N3S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
(1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H, 2.0 g, 10.41 mmol, 1.0 eq) was dissolved in H2O (12.5 mL). Then CH3CN (100 mL) was added at room temperature to the solution, followed by NaHCO3 (1.57 g, 18.73 mmol, 1.8 eq) and [(2-aminoethyl)amino]-N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}carboxamide (6.89 g, 14.57 mmol, 1.4 eq). After stirring overnight at room temperature, the reaction mixture was filtered to afford 3.27 g of the expected (1S,5R)-2-[N-(4-{[(2-aminoethyl)amino]carbonylamino}phenyl)carbamoyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:51])[NH:43][C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:51])[NH:43][C:44]3[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=3)[CH2:22][CH2:21][C@:20]3([CH3:52])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:53])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:56])([CH3:1])[C:3]([OH:5])=[O:4])[C:15]3([CH3:54])[CH3:55])[C:24]=12)([CH3:39])[CH3:38]
Reactant: Cc1ccc(NC(=O)/C=C/[C@@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]6CC[C@]54C)C2=C(C(C)C)C(=O)C3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)/C=C/[C@@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]6CC[C@]54C)C2=C(C(C)C)C(=O)C3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-(p-tolylamino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (250 mg, 0.325 mmol) in dichloromethane (5 mL) stirred at rt was added TFA (0.025 mL, 0.325 mmol). The reaction mixture was stirred at rt for 1 h. Upon completion and work-up and purification the title compound was obtained as a trifluoroacetic acid salt (150 mg, 0.181 mmol, 55.8%) as a light white solid. 1H NMR (300 MHz, DMSO-d6) δ=9.70 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.83 (d, J=15.8 Hz, 1H), 6.08 (d, J=15.7 Hz, 1H), 4.53-4.32 (m, 1H), 3.30-3.11 (m, 1H), 2.90-2.73 (m, 1H), 2.55-2.51 (m, 1H), 2.35-0.75 (m, 51H); LC/MS: m/z calculated 713.5. Found 714.3 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([N:11]=[N+]=[N-])[CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C@H:6]1[O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.[Ni]>[C:1]([NH:4][C@@H:5]1[C@@H:10]([NH2:11])[CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C@H:6]1[O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Agent: [Ni]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1
Reaction time: 6.5 h

Procedure:
100 g (0.295 mol) ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate were dissolved in 800 ml ethanol and placed in a 21 steel autoclave together with 34 g Raney Nickel (Degussa) in 200 ml ethanol. The autoclave was closed rinsed twice with nitrogen and then set under 2 bar hydrogen pressure. Hydrogenation took place at a temperature of 20-25° C. under mechanical stirring a 1000 rpm until, after all the starting material had reacted, also the content of the “2-azido-5-amino intermediate” was ≦0.01% area (GC measurement) which was about 5-8 h. However, it was found that due to this “overhydrogenation” the “cyclohexene double bond” became hydrogenated, too.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=O)=[O:20]>ClCCl>[C:1]([O:9][C:18]1[C:19](=[O:20])[C:21]2[C:22](=[CH:27][CH:28]=[C:29]([F:31])[CH:30]=2)[N:23]([CH3:26])[CH:24]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1ccc(F)cc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of benzoic acid (6.7 g) and triethylamine (9.9 ml) in dichloromethane (80 ml) was added to the solution of 2'-(2-chloroacetyl)-4'-fluoro-N-methylformanilide at 0°. The mixture was stirred at ambient temperature for 24 hours and then heated under reflux for 2 hours. The mixture was washed with water (2×50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue added to potassium carbonate (1.76 g) and dry dimethylformamide (30 ml). The mixture was heated under nitrogen at 60° for 6 hours. Further potassium carbonate (1.0 g) was added and the heating continued for 6 hours. The solvent was removed under reduced pressure at 60° C., the residue triturated with water (30 ml), and the solid collected by filtration to give the novel compound 6-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p. ]88°-190°.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:10]([CH3:21])[CH:9]([OH:8])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[CH:33][CH:32]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: Clc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 4-chloro-iodobenzene (0.24 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (4 ml) and ethanol (1 ml). The reaction mixture was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 3 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, from which the oxalate salt was made (0.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.070 g, 1.857 mmol), isoxazol-3-amine (0.158 ml, 2.135 mmol) and THF (12.38 ml) to give a clear solution. The flask was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.90 ml, 3.90 mmol) was added dropwise. After 10 min, the mixture was diluted with EtOAc and washed with 1N aq. HCl. The aq. layer was washed with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered; and concentrated. The residue was purified by chromatography (50-g SNAP Ultra column, 25-g silica gel loading column, 0-5% MeOH/DCM) to give 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.867 g) as a tan foam that was ca. 90% pure. m/z (ESI) 476.1 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>CS(C)=O>[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Temperature: 90 °C

Procedure:
Sodium cyanide (1.2 g) dissolved in dimethylsulphoxide was heated at 90° C. for 30 min. Solid 1-t-butyldimethylsilyloxy-6-bromohexane (5.8 g, compound X1) prepared according to the method previously described (ref. 37), then was added into the sodium cyanide solution. After heating at 120-130° C. for 20-180 min, the reaction mixture was poured into ice-cold water and the aqueous layer was extracted with ether, washed with brine, dried and concentrated. The product was distilled at 0.5 Torr and 107° C. to give a colourless oil. High resolution mass spectrometer for C12 H24 O N Si: calculated 226.1627, found 226.1624.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:32]=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=3)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]=[C:33]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=4)=[CH:27][CH:26]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Yield: 99.7 %

Procedure:
The product from example 40C (1.37 g, 2.153 mmol), in ethanol (10 mL) and THF (10 mL) then added platinum(IV) oxide (196 mg, 0.862 mmol) and a hydrogen balloon and stirred the solution at room temperature for 48 h. The reaction was then treated according to the procedure in Example 39G to provide the title compound (1.3 g, 100%) as a mixture of stereoisomers.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([N:9]1[C:10]2[C:6](=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:7][C:8]1=[O:14])(=[O:23])[CH3:22]
Reactant: CC(=O)Oc1cccc2c1CC(=O)N2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2c1CC(=O)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
To a mixture of 4-(acetyloxy)-1,3-dihydro-2H-indol-2-one (J. Med. Chem., 38:2802-2808, 1995; 1.44 g, 7.5 mmol) and sodium carbonate (5.3 g, 50 mmol) in tetrahydrofuran (50 mL) is added acetic anhydride (4.3 mL, 45 mmol). The mixture is stirred at ambient temperature for 18 hours, and partitioned between ethyl acetate and water. After drying (magnesium sulfate), the solvent is removed in vacuo. The crude material is preadsorbed on silica gel (10 g), and purified by flash chromtography (90 g SiO2, 10% ethyl acetate:hexane to 70% ethyl acetate:hexane, linear gradient over 30 minutes) to provide 480 mg (27%) of acetic acid 1-acetyl-2-oxo-2,3-dihydro-1H-indol-4-yl ester as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O[C@@H:23]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C>ClCCl>[C:26]([O:25][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:23]1[O:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: Oc1cccc2occ(CCc3ccccc3)c12
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 4-hydroxy-3-(2-phenylethyl)benzofuran (0.11 g) and 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranose (0.37 g) in dichloromethane (5 mL) was added boron trifluoride-diethyl ether complex (0.12 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-3-(2-phenylethyl)benzofuran (0.13 g). This material was dissolved in methanol (5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.043 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (24 mg).
Reaction SMILES: C12(C3C=CC(OC[C:17]4[O:18][C:19]5[CH:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][C:20]=5[N:21]=4)=CC=3)CC3CC(CC(C3)C1)C2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][C:26]([C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[CH:17][O:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccco1)c1ccc2ncoc2c1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (30.1 mg, 0.08 mmol), furfuryl amine (11.0 mg, 0.12 mmol, 0.01 ml), EDC (21.7 mg, 0.12 mmol) and HOBt (15.4 mg, 0.12 mmol) in DMF 3.0 mL was added DIPEA (14.2 mg, 0.12 mmol, 0.02 ml). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=6:3:1) to give 2-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan-2-ylmethyl)-amide as a white solid (6.3 mg, 17.4% yield).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:19]3[S:20][CH2:21][CH2:22][N:18]3[N:17]=2)[C:10]=1[F:30])C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:30][C:10]1[C:11]([C:16]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:19]3[S:20][CH2:21][CH2:22][N:18]3[N:17]=2)=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1nn2c(c1-c1ccncc1)SCC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(-c2nn3c(c2-c2ccncc2)SCC3)c1F
Temperature: 120 °C

Procedure:
To dibenzyl-[2,4-difluoro-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-amine (180 mg, 0.34 mmol) in toluene (2 mL) was added trifluoro-methanesulfonic acid (3.5 mL) in a sealable vial under nitrogen atmosphere. The mixture was stirred under microwave irradiation at 120° C. for ten minutes. The crude was diluted with ethyl acetate and washed with NaHCO3 saturated solution twice. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was isolated by column chromatography eluting with ethyl acetate: hexane (1: 1) (115 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[C:4]([F:14])[CH:3]=1.[OH-].[Na+].O.[BrH:18]>C(O)(=O)C>[Br:18][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:14])[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)ccc1-c1csc(Br)n1
Reaction time: 8 h
Yield: 98 %

Procedure:
2-(4-Bromo-2-fluorophenyl)-2-oxoethyl thiocyanate (2.1 g, 7.6 mmol), prepared in the previous step, in 15 mL of 33% hydrogen bromide in acetic acid was stirred overnight. The reaction was neutralized with 60 mL of 2N NaOH and 60 mL of water. The resulting residue was collected by suction filtration and placed under high vacuum to give 2.6 g of a brown paste. The crude product was purified on silica gel using a stepwise gradient of 5-20% ethyl acetate:hexane to give 2-bromo-4-(4-bromo-2-fluorophenyl)-1,3-thiazole (2.5 g, 98%), MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:25]4=[O:31])=[C:19]([CH3:32])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:34][CH2:35][Cl:36])[C:25]4=[O:31])=[C:19]([CH3:32])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(O)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(OCCCl)c1=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
900 mg (1.89 mmol) of the compound from Example 72A and 1.36 g (9.49 mmol) of 1-bromo-2-chloroethane are dissolved in 30 ml of 1-methyl-2-pyrrolidone. 1.55 g (4.75 mmol) of caesium carbonate are added to the solution, and the mixture is stirred at 60° C. for 15 hours. Water is then added, and, after phase separation, the aqueous phase is extracted three times with tert-butyl methyl ether and three times with dichloromethane. The combined organic phases are washed successively with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and then dried over sodium sulphate. The drying agent is filtered off and the solvent is removed completely on a rotary evaporator. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:5). This gives 464 mg (45% of theory, purity according to LC-MS 74%) of the desired product.