Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:46][CH3:47])[C:34]([NH:39][C@@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]=1[CH2:37][CH3:38].[CH3:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1B(O)O>>[CH2:46]([C:33]1[C:34]([NH:39][C@@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]([CH2:37][CH3:38])=[C:31]([C:50]2[CH:51]=[CH:52][C:53]([O:55][CH3:56])=[CH:54][C:49]=2[CH3:48])[N:32]=1)[CH3:47]
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CCc1nc(N[C@@H]2COC[C@H]2O)c(CC)nc1Br
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1COC[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting trans-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and 2-methyl-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3363, 1603, 1571, 1490, 1447, 1393, 1303, 1233, 1208, 1177, 1170, 1103, 1059, 887, 849 cm−1; OAMS supporting ions at: ESI+ 358.1; MS (EI) m/z 357 (M+); HRMS (FAB) calcd for C20H27N3O3+H1 358.2130, found 358.2142.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[Cl:22][C:23]1[C:24]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:36]2[CH2:37][CH2:38][N:33]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([C:29]([F:32])([F:31])[F:30])=[CH:26][N:25]=3)[CH2:34][CH2:35]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS m/z=473 (M+H)+.
Reaction SMILES: C([O-])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:11][C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([OH:21])=[C:14]([C:22](=[O:25])[CH2:23][CH3:24])[CH:13]=1.[C:26](Cl)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=1)[O:21][C:24]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:23]([CH3:26])[C:22]2=[O:25]
Reactant: CCC(=O)c1cc(Cl)cc(C(=O)O)c1O
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2ccccc2)oc2c(C(=O)O)cc(Cl)cc2c1=O
Yield: 90.9 %

Procedure:
A 47.5 g (0.33 mole) quantity of sodium benzoate was added with stirring to a mixture of 22.9 g (0.10 mole) of 5-chloro-3-propionylsalicylic acid and 42.1 g (0.30 mole) of benzoyl chloride. The reaction mixture was heated at 180° to 190° C. in an oil bath for 8 hours and was cooled. Thereto was added a 5% aqueous solution of sodium carbonate to dissolve the reaction mixture therein. The insolubles were filtered off. The solution was acidified with dilute hydrochloric acid and the separated white crystals were filtered off. The crystals were washed with an aqueous solution of alcohol and dried to obtain 28.6 g (90.9%) of white powder which had a melting point of 309° to 312° C. (sublimation). The compound thus obtained was subjected to chemical analysis with the results shown in Table 1 given below.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].I[CH3:16]>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[N:7]2[CH3:16]
Reactant: O=C1CNc2c(F)cccc2N1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (415 mg, 2.5 mmol) in THF (10 ml) was added sodium hydride (60%, 100 mg, 2.5 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled again in an ice/water bath and iodomethane (156 μl, 2.5 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred for 3 days. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 45:55) to give a white solid; yield 210 mg, 47%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[Cl-].C[NH3+].[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([NH:32][CH3:31])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1ncc(-c2ccc(OCC(=O)O)cc2)cc1-c1nc2ccccc2s1
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COc1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenoxyacetic acid (20 mg, 0.050 mmol) in DMF (1.0 mL) were added methylammonium chloride (4 mg, 0.06 mmol), TBTU (19 mg, 0.060 mmol) and DIEA (0.05 mL, 0.3 mmol). The mixture was left to stir at rt for 30 min. Purification via MDP afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.67 (d, J=4.8 Hz, 3H), 4.51 (s, 2H), 7.04-7.10 (m, 2H), 7.45-7.52 (m, 1H), 7.54-7.59 (m, 1H), 7.63-7.68 (m, 2H), 7.97 (s, 2H), 8.10 (d, J=7.8 Hz, 1H), 8.13-8.17 (m, 2H), 8.48 (d, J=2.3 Hz, 1H). MS (ES+): m/z=391.10 (100) [MH+]. HPLC: tR=3.20 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:24]=[CH:23]N=C1.C(Cl)(=O)C.Cl.[NH2:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:30]([CH:31]3[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]3=[O:38])[C:23]([CH3:24])=[N:1]2)=[CH:7][CH:8]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1nc2cc(CNC(=O)OC(C)(C)C)ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a stirred solution of 2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid (24.75 g, 92.94 mmol), imidazole (7.59 g, 111.53 mmol) in acetonitrile (300 mL), was added acetyl chloride (7.96 mL, 111.53 mmol), and the mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (15.30 g, 92.94 mmol), imidazole (12.66 g, 185.89 mmol) and triphenyl phosphite (29.23 mL, 111.53 mmol), and the mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature and the brown mixture was filtered. The filtrate was evaporated and then purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-7-ylmethyl]-carbamic acid tert-butyl ester as a light yellow solid (24.57 g, 66% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CF3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.97 min (99.7%); mp, 240-242° C.; 1HNMR (DMSO-d6) δ 1.29 (brs, 1H, CH from the BOC group), 1.40 (s, 8H, 8CH from the BOC group), 2.11-2.19 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.26 (d, J=6 Hz, 2H, CH2NH), 5.25 (dd, J=5, 11 Hz, 1H, CH), 7.35-7.99 (m, 4H, Ar and NHCH2), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.97, 23.49, 28.19, 30.60, 43.22, 56.48, 78.00, 118.84, 123.99, 125.41, 126.00, 146.93, 147.55, 155.15, 155.81, 160.29, 169.51, 172.61. LCMS MH=401; Anal Calcd For C20H24N4O5: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.78; H, 5.78; N, 13.85.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[CH3:36]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:25][C:24]=3[CH3:36])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6- [4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:20][C@H:12]2[CH2:13][N:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C@@:11]2([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH:38][CH3:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:20][C@H:12]2[CH2:13][N:14]([CH2:16][C:17]([N:38]([CH3:39])[CH3:37])=[O:18])[CH2:15][C@@:11]2([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(CC(=O)O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1C[C@@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution the product from Step A (37 mg, 0.072 mmol), dimethylamine (0.0433 mL, 0.0866 mmol, 2 M in THF), EDAC (18 mg, 0.0938 mmol), HOBt (19.51 mg, 0.144 mmol) and DIPEA (0.0252 mL, 0.144 mmol) in DMF (3 mL) was stirred at rt over the weekend. The reaction was quenched by addition of brine, extracted with EtOAc, dried over Na2SO4 and purified by CombiFlash (eluent: 8% methanol in DCM) to give the product as a yellowish gel. 1H-NMR (400 MHz, CDCl3): δ 1.29-1.43 (m, 9H), 1.75-2.09 (m, 4H), 2.20-2.35 (m, 1H), 2.55-2.71 (m, 3H), 2.86-3.00 (m, 4H), 3.05-3.22 (m, 6H), 3.60-3.93 (m, 2H), 4.25 (d, J=5.6 Hz, 1H), 4.59-4.92 (m, 3H), 7.70 (s, 1H), 8.70 (s, 1H); LC/MS: C26H36F3N5O4: m/z 540.3 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1F.[NH:30]1[CH2:36][CH2:35][CH2:34][C@@H:31]1[CH2:32][OH:33].C(N(C(C)C)CC)(C)C.O>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:30]3[CH2:36][CH2:35][CH2:34][C@@H:31]3[CH2:32][OH:33])[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: OC[C@H]1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@@H]3CO)ccc2c1=O

Procedure:
A mixture of EXAMPLE 1B (2.96 g), (R)-prolinol (850 μL) and diisopropylethylamine (4 mL) in acetonitrile (70 mL) at 25° C. was stirred for 3 days, treated with water, and filtered.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:12]1(=[O:24])(=[O:23])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][NH:15][CH2:14][CH2:13]1>>[O:23]=[S:12]1(=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:14][CH2:13]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: Clc1nc(Cl)c2sccc2n1
Product: NCCCNc1nc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamne, followed by reaction with 2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 404, 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.04 (d, J=7.3 Hz, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.46-7.57 (m, 2H), 7.34-7.42 (m, 1H), 7.10 (d, J=5.3 Hz, 1H), 5.19 (br. s., 2H), 3.76 (br. s., 2H), 3.44-3.54 (m, 4H), 3.00 (t, J=6.1 Hz, 2H), 1.88 (m, 2H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH:5](=[N:4]/[CH2:3][CH2:1][OH:2])\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCO
Reactant: O=Cc1ccccc1
Solvent: CO
Product: OCC/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88.1 %

Procedure:
To a solution of ethanolamine (1.23 g, 20.1 mmol) in anhydrous MeOH (50 mL) at 0° C. was added benzaldehyde (2.13 g, 20.0 mmol) and molecular sieves (10 pieces). The resulting mixture was gradually warmed to room temperature and stirred for 120 h. The reaction mixture was filtered while rinsing with CH2Cl2. The filtrate was evaporated, and the residue was dried under vacuum overnight to afford off-white oily Compound 1 (2.63 g, 87%). The compound was used for the next step without further purification. 1H NMR (CDCl3) δ 2.40 (s, 1H), 3.70 to 3.80 (m, 2H), 3.85 to 4.0 (m, 2H), 7.35 to 7.50 (m, 3H), 7.68 to 7.79 (m, 2H), 8.32 (s, 1H); 8.11 (d, 2H); 13C NMR (CDCl3) δ 62.28, 63.17, 128.1, 128.52, 130.78, 135.72, 163.10.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:43]([O:47][CH2:48][CH3:49])(=[O:46])[CH:44]=[CH2:45]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:2]=1/[CH:45]=[CH:44]/[C:43]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OC(F)(F)F)ccc1N
Temperature: 120 °C

Procedure:
To a mixture of 2-bromo-4-(trifluoromethoxy)aniline (1.00 mmol), triethylamine (1.5 mmol) and P(o-tol)3 (0.40 mmol) in DMF (0.5 M) in a glass pressure tube under nitrogen gas were added ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol). The tube was sealed and heated to 120° C. for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time (min)=2.467, method [1], MS (ESI) 276.1 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:39]1[CH:40]=[CH:41][CH:42]=[C:37]([NH-:36])[CH:38]=1
Reactant: Nc1cccnc1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [NH-]c1cccnc1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 188 mg (2 mmol) of 3-aminopyridin were added. After stirring for 3 hours, the starting borrelidin (Rf=0.43) disappeared and the product (Rf=0.25) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 95:5). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of dichloromethane and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 1:9 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (144 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.
Reaction SMILES: Cl.[NH2:2][OH:3].CC([O-])=O.[Na+].[C:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[CH:14][C:13]=1[OH:20])(=O)[CH3:10].CCO>O>[Br:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([CH2:9][CH:10]=[N:2][OH:3])=[C:13]([OH:20])[CH:14]=1
Reactant: CC(=O)c1cc(C)c(Br)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC=NO)c(O)cc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of hydroxylamine hydrochloride (400 mg, 5 8 mmol) in 1 ml water was added to a solution of NaOAc in 1 ml water. To the resulting solution was added 1-acetyl-4-bromo-2-hydroxy-5-methylbenzene (101) (1.14 g, 5 mmol) followed by addition of 15 ml EtOH. The reaction mixture was stirred at 80° C. for 1 h. After concentrated to half of it's volume, the reaction mixture was poured in to 60 ml ice-water. Precipitate formed was filtered, washed with water and dried to give 1.19 g (yield: 97.5%, purity>95%) 5-bromo-2-((hydroxyimino)ethyl)-4-methylphenol (102) as white solid.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[O:20]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[H-].[Na+].Br[CH2:37][CH2:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>CN(C=O)C.C(Cl)Cl.CO>[Si:39]([CH:38]([OH:20])[CH2:37][O:5][C@@H:4]1[C@@H:6]([CH2:7][OH:8])[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@@H:2]1[OH:3])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: CC(C)(C)[Si](C)(C)CCBr
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)C(O)CO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Adenosine (10 g, 37.42 mmol) was dried over P2O5 under high vacuum. It was then suspended in anhydrous DMF (150 mL) and NaH (1.35 g, 56.13 mmol) was added. The reaction mixture was stirred at room temperature under inert atmosphere for 30 min. Then (2-bromo ethyl)-tert-butyldimethylsilane (9.68 mL, 4.4.90 mmol) was added dropwise and the reaction mixture stirred at room temperature overnight. DMF was removed under vacuum and to the residue dichloromethane (100 mL) was added and washed with water (2×80 mL). Dichloromethane layer was dried over anhydrous Na2SO4 and evaporated to dryness. Residue purified by column to get a mixture of the title compounds (4.30 g). Rf 0.49, 0.57 (10% MeOH in CH2Cl2)
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[C:12]4[S:19][CH:18]=[N:17][C:13]4=[CH:14][CH:15]=3)[C:10]3([C:31]4[C:22](=[CH:23][C:24]5[O:29][CH2:28][CH2:27][O:26][C:25]=5[CH:30]=4)[O:21][CH2:20]3)[C:9]2=[O:32])=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[S:19]1[C:12]2=[C:11]3[C:16](=[CH:15][CH:14]=[C:13]2[N:17]=[CH:18]1)[NH:8][C:9](=[O:32])[C:10]13[C:31]2[C:22](=[CH:23][C:24]3[O:29][CH2:28][CH2:27][O:26][C:25]=3[CH:30]=2)[O:21][CH2:20]1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3c2ccc2ncsc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a solution of 6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one (1.9 g, 4.0 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (40 mL) was added at ambient temperature trifluoromethanesulfonic acid (1.8 mL, 20 mmol). The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo Water was added to the residue and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography and eluted with 50% ethyl acetate in hexanes to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one (0.65 g, 44%): 1H NMR (300 MHz, CDCl3) δ10.86 (s, 1H), 9.06 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 6.21 (s, 1H), 4.68 (s, 2H), 4.19-4.01 (m, 4H); MS (ES+) m/z 353.1 (M+1).
Reaction SMILES: [Br:1][C:2]1([CH3:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[NH2:14][C:15]([NH2:17])=[S:16]>>[BrH:1].[NH2:17][C:15]1[S:16][C:2]2([CH3:13])[CH2:10][C:9]3[CH:8]=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=3[C:3]2([OH:12])[N:14]=1
Reactant: NC(N)=S
Reactant: CC1(Br)Cc2cc(Cl)ccc2C1=O
Product: Br
Product: CC12Cc3cc(Cl)ccc3C1(O)N=C(N)S2

Procedure:
1.5 g of 2-bromo-5-chloro-2-methylindan-1-one are dissolved together with 460 mg of thiourea in 50 ml of triacetone and boiled under reflux for 8 h. The precipitate is filtered off with suction, washed with acetone and dried in vacuo. 2-Amino-6-chloro-8a-methyl-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol hydrobromide is obtained and melts at 229° C. with decomposition.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([O:12][CH2:13][CH3:14])([CH3:11])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([O:12][CH2:13][CH3:14])([CH3:11])[C:8]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C)(C(=O)O)c1ccc(-c2ccccc2)cc1
Product: CCOC(C)(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
(RS)-2-Biphenyl-4-yl-2-ethoxy-propionic acid was coupled with 4-aminomethyl benzonitrile to give (RS)-2-biphenyl-4-yl-N-(4-cyano-benzyl)-2-ethoxy-propionamide according to general procedure C. Colorless solid. MS 385.1 ([M+H]+)
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[N:21][OH:22])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=CCn1cc(Cc2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CCn1cc(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the aldehyde from Step 2 (390 mg, 1.57 mmol) in EtOH (6 mL) there was added hydroxylamine hydrochloride (435 mg, 6.26 mmol), then pyridine (3 mL). The mixture was stirred at r.t. for 45 minutes, then it was evaporated to dryness. The residue was partitioned between Et2O and H2O, and by evaporation of the ethereal fraction the title oxime was obtained as a soft solid.