Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][S:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)[O-].[K+]>O>[CH:4]([CH:6]1[CH2:10][S:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5]
Reactant: CON(C)C(=O)C1CSC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C(C=O)CSC1(C)C
Reaction time: 1 h

Procedure:
A flask containing tert-butyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethylthiazolidine-3-carboxylate (2), 0.918 g, 3 mmol and diethyl ether (20 mL) was cooled in an ice bath. To the cooled solution, lithium aluminum hydride (160 mg, 4.2 mmol) was added. After 1 h additional ether (20 mL) was added. After an additional 1 h, a solution of potassium bisulfate (315 mg) in water (1 mL) was added carefully to the reaction. Celite was added, the mixture was filtered, and the solids were rinsed with additional ether. The collected ether was washed with 0.1 N HCl(aq) (15 mL), saturated sodium bicarbonate (15 mL), and brine (15 ml). The ether was dried over Na2SO4, evaporated and used without further purification. Yield 684 mg (92%)
Reaction SMILES: C([N:14]1[CH2:17][C:16]([OH:21])([C:18]([OH:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:22]>O1CCOCC1.[Pd]>[ClH:22].[OH:21][C:16]1([C:18]([OH:20])=[O:19])[CH2:17][NH:14][CH2:15]1
Reactant: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1(O)CNC1
Yield: 82 %

Procedure:
To a solution of 2.383 g (8.4 mmoles) of crude 1-benzhydryl-3-hydroxyazetidine-3-carboxylic acid in 64 ml of 50% aqueous dioxane is added 2.1 ml of concentrated hydrochloric acid, and the mixture is catalytically hydrogenated for 32 hours in the presence of 924 mg of 10% palladium-charcoal under hydrogen pressure of 5 kg/cm2. The catalyst is filtered off and washed with an aqueous dioxane. The combined filtrate and washings are evaporated under reduced pressure during which the precipitating oily material is removed by washing with ether. The residue is washed with acetone and recrystallized from dimethylformamide-acetone to yield 1.051 g of 3-hydroxyazetidine-3-carboxylic acid hydrochloride as prisms in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[C:3]=1[Cl:16].N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)\[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[C:3]=1[Cl:16]
Reactant: CN1CCc2[nH]c3ccc(Cl)c(Cl)c3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3c(Cl)c(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8,9-Dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.78 mmol) was dissolved in DMF. Copper (I) iodide (14 mg, 0.078 mmol), L-proline (17 mg, 0.156 mmol) and potassium phosphate (330 mg, 1.56 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (200 mg, 0.94 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.50 (m, 2H), 7.25 (m, 1H), 7.10 (t, 2H), 7.05 (d, 1H), 6.75 (s, 1H), 5.10 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.38 (m, 1H), 3.22 (m, 1H), 3.05 (s, 3H), 2.90 (m, 1H), 1.90 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][C:8]4[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:9][C:8]4[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3c(-c4ccccc4)cc4c(c3c2c1)C(=O)NC4=O
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2c1cc(-c1ccccc1)c1[nH]c3ccc(O)cc3c21
Yield: 89 %

Procedure:
Demethylation of 820 prepared as described in example 419 with BBr3 using the procedure described in example 80 gave (821) (89%), mp 335–345° C. 1H NMR δ [(CD3)2SO] 11.50 (s, 1H), 11.10 (s, 1H), 9.26 (d, J=2.4 Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 7.77–7.75 (m, 2H), 7.65–7.61 (m, 3H), 7.56–7.52 (m, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H). Found: C, 72.71; H, 3.55; N, 8.16. C20H12N2O3 requires: C, 73.16; H, 3.68; N, 8.53.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:19][Si](CC)(CC)CC)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:12])([F:13])[F:14])[C:15]([F:16])([F:17])[F:18])=[CH:8][CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 0.5 g (1.24 mmol) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine in 2 mL of DMF were added 0.3 mL (2.5 mmol) of benzylbromide and the mixture was stirred overnight at 80° C. After distribution between a 2M aqueous solution of NaOH and Et2O, drying of the combined organic phases over Na2SO4 and evaporation, the resulting crude was dissolved in 5 mL of MeOH, treated with 1 mL of a 2M NaOMe-solution in MeOH and stirred for 30 min. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 95:5 gave 0.33 g (70%) of 2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow semisolid, MS: 378 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:26]([O:30][N:31]1N=NC2C=CC=N[C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C=O)C>[CH3:26][O:30][N:31]([CH3:32])[C:18]([C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)=[O:19]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 6.5 mmol) was taken into DMF (10 mL) followed by addition of HATU (2.48 g, 6.5 mmol), N,N-diisopropylethylamine (2.5 mL, 14.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (652 mg, 6.7 mmol), and the mixture was stirred at room temperature over 12 hours. The resulting solution was partitioned with ethyl acetate and water then the organic phase washed with water (3×), 10% aqueous citric acid (2×) then 0.5M aqueous sodium hydroxide and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated, then purified by silica gel flash chromatography with ethyl ether as eluent to provide tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (1.45 g). MS (EI) for C17H26N4O4: 351 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[N:19]([CH3:24])[C@@H:18]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16].[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][C@@H:38]([CH2:41]I)[CH2:39][CH3:40]>C1COCC1>[CH3:13][O:14][C:15]([N:17]1[CH2:22][CH:21]([CH2:41][CH:38]([CH2:37][C:31]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=2[F:29])[CH2:39][CH3:40])[C:20](=[O:23])[N:19]([CH3:24])[CH:18]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16]
Reactant: CC[C@H](CI)Cc1ccc(F)cc1F
Reactant: COC(=O)N1CCC(=O)N(C)[C@@H]1C(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(Cc1ccc(F)cc1F)CC1CN(C(=O)OC)C(C(C)(C)C)N(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A flask was charged with 1.35 mL (9.64 mmol) of diisopropyl amine and 15 mL of dry THF. The solution was cooled to −78° C. and 6.0 mL (9.64 mmol) of 1.6 M n-butyl lithium solution in hexanes was added. The mixture was warmed to 0° C. and stirred for 30 minutes. The mixture was cooled again to −78° C. and 2.0 g (8.76 mmol) of (2S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester was added as a solution in 10 mL of THF. This mixture was warmed to 0° C. and stirred for 1 hour. The anion solution was cooled again to −78° C. and 2.99 g (9.64 mmol) of (S)-2,4-difluoro-1-(2-iodomethyl-butyl)-benzene was added as a solution in THF. The mixture was stirred at −78° C. for 4 hours. The reaction mixture was warmed to −21° C. and stirred at that temperature for 5 days. The reaction mixture was quenched with sat. aq. ammonium chloride solution. The crude reaction mixture was extracted with diethyl ether. The ether was removed under reduced pressure, and the crude residue was purified by column chromatography (9:1 hexanes/EtOAc eluent) which gave 1.67 g (46% yield) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=23)=[C:4]([F:22])[CH:3]=1.Cl.Cl.N1C2C(=NC=CC=2OC2C=CC(N[C:42]([NH:44][C:45](=[O:55])[CH2:46][C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3Cl)=[S:43])=CC=2F)C=C1.C1(CC(N=C=S)=O)C=CC=CC=1>>[ClH:53].[F:22][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:44][C:45](=[O:55])[CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:43])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: Cl
Agent: O=C(Cc1ccccc1)N=C=S
Product: COC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 72 %

Procedure:
Starting from the amine 287, following the procedure described above for the synthesis of compound 269b (scheme 561, example 222) and replacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacetyl isothiocyanate, title compound 288 was obtained in 72% yield as a yellowish solid. 1H NMR (d-DMSO) δ (ppm): 12.51(s, 1H), 11.84(s, 1H), 8.64(dd, 1H, J1=5.1 Hz, J2=0.4 Hz), 8.24(s, 1H, J=0.4 Hz), 8.02(dd, 1H, J1=1.8 Hz, J2=13.4 Hz), 7.56-7.54(m, 2H), 7.36-7.31(m, 1H), 7.28-7.25(m, 1H), 6.81 (d, 1H, J=5.5 Hz), 3.91 (s, 3H), 3.81 (s, 2H). MS (m/z):496.3 (M+H) (found).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22](B5OC(C)(C)C(C)(C)O5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2].Br[C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.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].ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22]([C:41]5[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(B5OC(C)(C)C(C)(C)O5)CC4)cc3)oc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(c5ccc(C(F)(F)F)cn5)CC4)cc3)oc12
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a mixture of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]methyl}benzamide (70 mg, 0.133 mmol, INTERMEDIATE 9), 2-bromo-5-(trifluoromethyl)pyridine (45 mg, 0.199 mmol), and cesium carbonate (130 mg, 0.400 mmol) in tetrahydrofuran (6 ml) and water (0.6 ml) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (7 mg, 8.57 mmol). The mixture was heated to reflux and stirred at this temperature overnight. The reaction mixture was cooled and added directly to a 25 samplet, and then purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes, to provide the title compound (35 mg, 0.064 mmol, 48.2% yield). Mass spectrum (ESI) 545.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.34 (d, J=8.5 Hz, 2H); 7.97 (d, J=8.5 Hz, 2H), 7.94 (d, J=1.0 Hz, 1H); 7.85 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.83, (br s, 1H), 6.37 (br t, J=5.5 Hz, 1H), 3.54 (br t, J=4.5 Hz, 2H), 3.48 (septet, J=6.5 Hz, 1H), 2.75 (br d, J=16.5 Hz, 1H), 2.53 (br d, J=15.5 Hz, 2H), 2.04-2.16 (m, 3H), 1.50-1.68 (m, 3H), 1.46 (d, J=7.0 Hz, 6H), 1.25 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32]C)=[O:30])=[CH:21]\[C:22]2C=C[CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].O=C(CC1[S:47]C=CC=1)C(OC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH3:32])=[O:30])=[CH:21]\[C:22]2[S:47][CH:25]=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Cc1cccs1
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: COC(=O)/C(=C/c1cccs1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 23 %

Procedure:
The title compound was prepared as described for C4 using methyl 2-oxo-3-(thiophen-2-yl)propanoate B13 (Otava, 100 mg, 0.543 mmol), sodium hydride (13.03 mg, 0.373 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (223 mg, 0.543 mmol). The compound was isolated in the form of white solid in 23% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].CCN(C(C)C)C(C)C.[OH:38][C:39]1([C:50]([F:53])([F:52])[F:51])[CH2:45][CH:44]2[N:46](C(Cl)=O)[CH:41]([CH2:42][CH2:43]2)[CH2:40]1>C1COCC1.CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([N:46]4[CH:44]5[CH2:43][CH2:42][CH:41]4[CH2:40][C:39]([C:50]([F:51])([F:52])[F:53])([OH:38])[CH2:45]5)=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Reactant: O=C(Cl)N1C2CCC1CC(O)(C(F)(F)F)C2
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 69.9 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.1 g, 3.1 mmol) and DIPEA (2.7 mL, 16 mmol) in THF (10 mL) and NMP (5 mL) was added 3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carbonyl chloride (reagent preparation 37, 0.81 g, 3.1 mmol). The reaction mixture was heated (50° C.) for four hours and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography provided 8-{[7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4 (5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (1.1 g, 69% yield) as red oil. MS (ES) for C23H24F3N5O5: 507.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(N)cc1

Procedure:
1-(4-Amino-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester was prepared from 1-(4-nitro-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester followed the procedure of Example 1 Step 1: 1H NMR (DMSO-d6) δ 1.10 (t, J=7.2 Hz, 3H), 4.20 (q, J=7.2 Hz, 2H), 5.01 (br s, 2H), 5.55 (s, 2H), 6.45 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 7.16-7.20 (m, 3H), 7.35 (td, J=7.3, 1.0 Hz, 1H), 7.62 (dd, J=5.2, 1.2 Hz, 1H), 7.65 (d, J=4.1 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H); MS (ESI) m/z 377 (MH+); 375 ([M−H]−); Anal. calcd for C22H20N2O2S.0.05 TFA C, 69.46; H, 5.29; N, 7.33. Found: C, 69.66; H, 5.04; N, 7.72.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][CH2:19][C@:17]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[N:18]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([O:24][CH2:23][C@@H:21]1[O:20][CH2:19][C@:17]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:18]=[C:13]([NH:12][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:32])[S:14][CH2:15][C@@H:16]2[CH2:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COS(C)(=O)=O)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (36.2 μL, 0.474 mmol) was added drop-wise to a 0° C. solution of tert-butyl[(4aR,6R,8aS)-8a-(2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C18) (94 mg, 0.24 mmol) and triethylamine (0.198 mL, 1.42 mmol) in dichloromethane (1 mL). The reaction was allowed to warm to room temperature and stir for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) provided the product as a white solid. Yield: 86 mg, 0.18 mmol, 75%. LCMS m/z 475.4 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 9H), 1.60-1.68 (br m, 1H), 1.92-2.07 (br m, 1H), 2.56 (dd, J=12.9, 2.9 Hz, 1H), 2.93 (dd, J=12.7, 3.9 Hz, 1H), 3.07-3.19 (br m, 1H), 3.09 (s, 3H), 3.79 (d, J=12.1 Hz, 1H), 3.96-4.04 (m, 1H), 4.21 (dd, J=12.0, 1.5 Hz, 1H), 4.27 (dd, half of ABX pattern, J=11.3, 6.2 Hz, 1H), 4.32-4.38 (br m, 1H), 7.06-7.13 (m, 1H), 7.18-7.24 (m, 1H), 7.30-7.39 (br m, 2H).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cc2ccccc2n1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccccc2n1O
Yield: 59.5 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 6 except for using 3.99 g (22.5 mmol) of 1-hydroxy-2-indolecarboxylic acid, 5.36 g (45.0 mmol) of thionyl chloride and 100 ml of methanol. Thus 2.56 g (59.5%) of methyl 1-hydroxy-2-indolecarboxylate was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[NH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2>>[C:23]12([NH:22][C:16](=[O:18])[CH:15]([C:7]3[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=3)[CH3:21])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CC(C(=O)NC12CC3CC(CC(C3)C1)C2)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and 1-aminoadamantane were used to obtain N-Adamantyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[N:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[N:12][CH:13]=1.[B:23]1(B2OC(C)(C)C(C)(C)O2)[O:27]C(C)(C)C(C)(C)[O:24]1.C([O-])(=O)C.[K+]>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]>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][C:11]2[N:10]=[CH:9][C:8]([B:23]([OH:27])[OH:24])=[CH:13][N:12]=2)[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cnc(CCCCn2ccnn2)nc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: OB(O)c1cnc(CCCCn2ccnn2)nc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium(0) (0.027 g, 0.03 mmol in dioxane (6 ml) tricyclohexylphosphine (0.084 g, 0.30 mmol) is added and the mixture stirred under argon for 30 min. A solution of 5-bromo-2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.282 g, 1.0 mmol), bis(pinacolato)diboron (0.279 g, 1.1 mmol) and potassium acetate (0.147 g, 1.5 mmol) is added and the mixture is heated at 80° C. for 5 h. After cooling the mixture is concentrated in vacuo and the crude product is purified by flash column chromatography (ethyl acetate (100%)->ethyl acetate/tetrahydrofuran 1:1) yielding 2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine-5-boronic acid as a beige solid. Yield 140 mg (57%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2ccnc(Cl)n2)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
2,4 dichloropyrimidine was coupled to 3-nitrophenyl boronic acid following procedure A. The workup and purification protocol was modified as follows: The THF was removed from the reaction mixture by rotary evaporation and the residue taken up in ethyl acetate. The solution was washed with water followed by sat. NaCl and the organic layer concentrated by rotary evaporation until the product started to precipitate, at which point the flask was placed in an ice bath for two hours. The product was collected by filtration in a Buchner funnel. The yield was 60%. Product was >95% pure by LC-MS and showed the expected M+H+ of 236.