Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[CH:5]2.Br[CH:13]([CH2:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:13]([CH2:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Reactant: Oc1ccc2ncncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncncc2c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
6-Hydroxyquinazoline (0.060 g, prepared as described in J. Chem. Soc. (1952), 4985) and 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.101 g) were dissolved in dry N,N-dimethylformamide (2 ml) containing anhydrous potassium carbonate (0.088 g). The mixture was stirred and heated to 80° C. for 5 hours then allowed to cool to ambient temperature and stored for 18 hours. The brown suspension was diluted with water, extracted into ethyl acetate and the organic phase separated, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a pale brown oil. The oil was fractionated by chromatography (silica; ethyl acetate/hexane, 4:1 by volume) to give the title product (0.12 g) as a pale brown gum.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:7])[CH3:6])[C:2]#[CH:3].C(N)C#C.C(Cl)(=O)C.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:32][CH:31]=[N:30][C:29]=1[CH3:33]>ClCCl.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.CN(C=O)C.CCN(CC)CC>[F:16][C:17]1[C:18]([C:3]#[C:2][CH2:1][NH:4][C:5](=[O:7])[CH3:6])=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27][C:28]1[NH:32][CH:31]=[N:30][C:29]=1[CH3:33]
Reactant: C#CCNC(C)=O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCN
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC#Cc1c(F)ccc2c1C(=Cc1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N-propargylacetamide (32.8 mg, 0.34 mmol) (prepared by the reaction of propargyl amine (Aldrich) with acetyl chloride and triethyl amine in dichloromethane at 0° C. for 3 h) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give N-[3-[2,3-dihydro-5-fluoro-3-[(5-methyl-3H-imidazol-4-yl)methylene]-2-oxo-1H-indol-4-yl]-prop-2-ynyl]-acetamide. (Yield 35 mg, 77%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:24]C1C=C2C(C=C(C)C(C(O)C(OCC)=O)=C2O)=CC=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([Cl:24])=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1O
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1O

Procedure:
Prepared in a similar manner to ethyl 2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate of Example 120, except using ethyl 2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: (400 MHz, CDCl3): δ 9.01 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 5.49 (s, 1H), 4.22-4.08 (m, 2H), 2.56 (s, 3H), 1.31 (s, 9H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:16])=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl.[O-2].[Mn+2]>[CH2:1]([O:3][C:4]1[C:5]([CH:16]=[O:25])=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOCCOc1ccnc(C)c1OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCOCCOc1ccnc(C=O)c1OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
3-Ethoxy-4-(2-ethoxyethoxy)-2-methylpyridine (0.92 g, 4.09 mmol, obtained from Example 4(c)) dissolved in CH2Cl2 (5 mL) was added dropwise to m-CPBA (1.33 g, 4.50 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at r.t. for 16 h. CH2Cl2 (10 mL) was then added and the organic phase was washed with sodium carbonate (5% aq., 2×20 mL), dried (MgSO4) and evaporated in vacuo. The residue was dissolved in acetic anhydride (20 mL) and stirred at 130° C. for 1 h. The solvent was evaporated in vacuo and water (40 mL) was added to the residue. The pH was adjusted to pH 8 with 2M sodium hydroxide. The aqueous phase was extracted with CH2Cl2, dried (MgSO4) and evaporated. The residue was dissolved in ethanol (5 mL) and 2M sodium hydroxide (8 mL) was added. The mixture was stirred under reflux for 2 h. The solvent was evaporated and the residue partitioned between water and CH2Cl2. The organic phase was dried (MgSO4) and concentrated and the residue was dissolved in CH2Cl2 (10 mL) and manganese oxide (1.57 g, 18.06 mmol) was added. The mixture was then stirred under reflux under a nitrogen atmosphere overnight. The reaction mixture was filtrated through celite and concentrated, and the crude product was purified by flash chromatography (heptane/ethyl acetate; 1:1), giving the title compound (0.22 g, 22%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a 50 mL three-necked flask containing AlCl3 (4.406 g; 33.05 mmol) under N2, anisole (IVa) (4.467 g; 41.31 mmol) was added in one portion at RT. The reaction was exothermic. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (6.430 g; 27.54 mmol) was added drop wise keeping temperature below 20° C. Then the resulting red suspension was stirred at RT for 3h30. The red thick solution was poured under stirring into a mixture of ice and 1N HCl (100 mL), then the resulting white solid was filtered, and washed with water. The solid was washed with pentane (3×30 mL) and dried under vacuum at RT to give a white powder (m=8.51 g). Purification was performed by crystallization from acetone (30 ml) to give the title compound as a white powder (m=6.113 g) in a 73% yield.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:19])[C:8]=2[CH:20]=1.[C:21](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1>[C:15]([N:10]1[C:9](=[O:19])[C:8]2[CH:20]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=2[N:13]=[C:12]([O:14][CH3:21])[CH2:11]1)([CH3:17])([CH3:16])[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)N1CC(=O)Nc2ccc(Cl)cc2C1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COC1=Nc2ccc(Cl)cc2C(=O)N(C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 118.1 %

Procedure:
Methyl iodide (233 μL, 3.7 mmol) is added to a mixture of 7-chloro-4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (0.5 g, 1.9 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 16 hours, heated at reflux for 90 hours, filtered through diatomaceous earth and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 33% to 50% ethyl acetate in hexanes solutions gives the title product as a clear oil (0.63 g) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([CH:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C1([O:51]C)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH:17]([O:19][C:20](=[O:51])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: COc1ccccc1
Reactant: CC(OCc1ccccc1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OC(=O)c1ccccc1)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
To a solution of diphenylmethyl 7-(2-thienylacetamido)-3-(1-benzyloxyethyl)-3-cephem-4-carboxylate (stereoisomer A: 160 mg) in methylene chloride (1.6 ml) are added anisole (0.32 ml) and trifluoroacetic acid (0.32 ml). After 15 minutes, the reaction mixture is evaporated to dryness, and the obtained residue is dissolved in ethyl acetate. The solution is extracted with aqueous sodium hydrogen carbonate solution. The extract solution is evaporated with ethyl acetate, cooled with ice, stirred and neutralized with 1N-hydrochloric acid to pH 2.0, and is extracted with ethyl acetate. The extract solution is washed with saline, dried over sodium sulfate, and evaporated to give 7-(2-thienylacetamido)-3-(1-benzoyloxyethyl)-3-cephem-4-carboxylic acid (stereoisomer A: 60 mg). m.p. 114°-118° C. RF: same with the benzylamine salt described below.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:7][C:6]=1[OH:32])(=O)C.[ClH:33]>C(O)C>[ClH:33].[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:7][C:6]=1[OH:32]
Reactant: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(N)cc1C(C)(C)C

Procedure:
23.0 g of 2-acetylamino-4-t-butyl-5-hexadecyloxyphenol obtained in Example 1, 120 ml of ethanol and 96 ml of 35% hydrochloric acid were blended, and the mixture was refluxed for 5 hours with stirring. After cooling the reaction solution, the crystals formed were separated by filtration to obtain 23.2 g of 2-amino-4-t-butyl-5-hexadecyloxyphenol hydrochloride.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:45])[CH3:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)Cn1ccc(Br)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(CC(C)(C)O)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [m+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]C1C=CC=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Cc1ccccc1C[Mg]Br
Product: Cc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-methylbenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=388.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.ClCCl.[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45](Cl)=[O:46]>O1CCCC1.CN(C)C=O>[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)=[O:46]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)c5ccccc5Cl)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a suspension of 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (2.1 g, 5.29 mmol) in tetrahydrofuran (26 mL) at room temperature was added N,N-diisopropylethylamine (2.05 g, 15.87 mmol), dichloromethane (12 mL) and N,N-dimethylformamide (5 mL). To the resulting suspension was slowly added o-chlorobenzoyl chloride (1.02 g, 5.82 mmol), and the reaction mixture was stirred for 0.5 h at room temperature. The solution was concentrated in vacuo, the resulting residue diluted with acetic acid (7.5 mL) and water (0.5 mL), and the product purified by reverse phase preparative HPLC. The purified salt was partitioned between dichloromethane and 1M aqueous sodium hydroxide, the organic layer removed and the aqueous layer re-extracted with dichloromethane, and the combined organic layers washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a white foam (1.75 g, 3.26 mmol, 62%). (m/z): [M+H]+ calcd for C30H38ClN5O2) 536.28; found 536.3. 1H NMR (300 MHz, DMSO-d6): 0.90 (br m, 2H), 1.24 (d, 6H), 1.45 (br m, 2H), 1.68 (br m, 8H), 1.96 (m, 1H), 2.72 (br m, 5H), 3.08 (m, 2H), (3.20, m, 3H), 4.40 (br m, 1H), 7.14 (t, 1H), 7.28 (m, 2H), 7.39 (m, 1H), 7.49 (dd, 1H), 7.66 (dd, 1H).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23]O)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:25])=[O:4].[N:28]1C=CC=C[CH:29]=1.C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][NH:28][CH3:29])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:25])[CH3:26])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3cnc(CO)s3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
Mesyl anhydride (860 mg, 4.9 mmol) is added to 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-5-(4-(2-(hydroxymethyl)thiazol-5-yl)phenyl)-2,2-dimethyl-oxazolidin-3-yl)ethanone (1.4 g, 3.5 mmol) in CH2Cl2 (35 mL). Pyridine (0.5 mL, 5.9 mmol) is added and stirred at room temperature for 1 hour. The reaction is diluted with CH2Cl2 (35 mL) and washed with water and brine. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude mesylate is dissolved in acetonitrile (10 mL) and transferred to a scintillation vial. Diisopropylethylamine (0.65 mL, 3.7 mmol) and metyhlamine HCl (130 mg, 1.9 mmol) are added and the reaction mixture is heated to 55° C. for 18 hours. The reaction mixture is cooled and diluted with saturated NaHCO3 (75 mL). The reaction mixture is extracted with CH2Cl2 (2×75 mL) and the combined organic phase is dried (Na2SO4) and concentrated under vacuum to afford the title compound (475 mg): m/z (Cl) M+H 414.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:14][C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][C:12]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCc2c(N)ccc(Cl)c2CC1

Procedure:
A solution of 10 g (0.04 mol) of the nitro compound and 6.0 ml of hydrazine hydrate in 400 ml of ethanol was warmed to 45° while activated Raney nickel was added in small portions until the evolution of gas ceased. The mixture was cooled, filtered through a filter aid and concentrated to give 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[CH3:14][O:15][CH2:16][C:17]1([N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[C:34]1([CH2:44][CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>O>[CH3:14][O:15][CH2:16][C:17]1([N:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:21][N:20]([CH2:45][CH2:44][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[CH2:19][CH2:18]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccc3ccccc23)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A mixture of 6.4 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide and 5.5 parts of [2-(1-naphthalenyl)ethyl]4-methylbenzenesulfonate and the whole is stirred and refluxed for 20 hours. The reaction mixture is cooled to room temperature and poured onto water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in hexane. The product is filtered off and crystallized from a small amount of 2,2'-oxybispropane, yielding 2.8 parts (43.4%) of N-{4-(methoxymethyl)-1-[2-(1-naphthalenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 109.8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.[CH:24]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1>>[CH:33]1[C:34]2[N:35]([C:2]3[CH:7]=[CH:6][C:5]4[N:8]5[C:21]6[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=6[C:15]([CH3:23])([CH3:22])[C:14]6[C:9]5=[C:10]([CH:11]=[CH:12][CH:13]=6)[C:4]=4[CH:3]=3)[C:36]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: CC1(C)c2ccccc2-n2c3ccc(-n4c5ccccc5c5ccccc54)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 18 by reaction of 31 g (86.0 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]-acridine with 16 g (95.9 mmol) of carbazole.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([NH:19][CH2:20][C:21]4[C:22]([CH3:36])=[CH:23][C:24]([NH:28]C(=O)OC(C)(C)C)=[N:25][C:26]=4[CH3:27])=[O:18])[CH:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:37]>C(Cl)Cl>[NH2:28][C:24]1[N:25]=[C:26]([CH3:27])[C:21]([CH2:20][NH:19][C:17]([C:15]2[CH:14]=[N:13][N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[C:3]([CH3:37])=[CH:4]4)[CH:16]=2)=[O:18])=[C:22]([CH3:36])[CH:23]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3c(c2)cc(C)n3C)c1
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc3c(c2)cc(C)n3C)c1
Reaction time: 144 h

Procedure:
To a solution of tert-Butyl 5-((1-((1,2-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate (160 mg, 0.318 mmol) in DCM (5 ml) Silica gel (2000 mg) was added. The resulting suspension was concentrated under vacuum to dryness and kept at 75° C. for 6 days under high vacuum. The mixture was taken up in suspended in DCM/NH3 (in MeOH 7N) 9:1, the solution was filtered of and concentrated under reduced pressure to afford the title compound. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 ODB 5 um, 30×100 mm, 1 to 99% ACN and 0.1% TFA, flow 45 ml/min) to yield pure title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([CH3:29])[CH2:16][O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1F)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[F:24][C:23]1[C:18]2[O:17][CH2:16][C@@H:15]([CH3:29])[NH:14][C:19]=2[C:20]([N+:25]([O-:27])=[O:26])=[CH:21][CH:22]=1
Reactant: C[C@H](COc1c(F)ccc([N+](=O)[O-])c1F)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1COc2c(F)ccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
TFA (3 mL) was added to a solution of [(R)-2-(2,6-difluoro-3-nitrophenoxy)-1-methylethyl]carbamic acid tert-butyl ester (333 mg, 1.00 mmol) in DCM (15 mL) and the mixture was stirred for 90 min at rt. PhMe (25 mL) was added and the solution was concentrated in vacuo. The resultant residue was taken up in MeCN (7 mL); aqueous 2M Na2CO3 (7 mL) was added and the mixture was stirred vigorously for a further 90 min at rt. EtOAc (25 mL) and brine (25 mL) were added and the phases were separated. The aqueous was extracted with EtOAc (2×25 mL), and the combined organics were dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (Si—PPC, gradient 0-20% EtOAc in cyclohexane) to afford the title compound as a bright yellow solid (184 mg, 87%). 1H NMR (CDCl3, 300 MHz): δ 7.84 (1H, br s), 7.79 (1H, dd, J=9.8, 5.6 Hz), 6.45 (1H, app. t, J=9.8 Hz), 4.36-4.28 (1H, m), 3.84-3.76 (2H, m), 1.35 (3H, d, J=6.3 Hz)