Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=2[S:5][C:6]=1[C:7](=O)[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]2[C:20]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:18]=[C:17]([O:27][CH3:28])[C:15]=2[N:16]=1)=O.FC(F)(F)C([O-])=O.[NH4+:41]>O>[CH3:28][O:27][C:17]1[C:15]2[N:16]=[C:12]([C:10]3[NH:41][C:7]([C:6]4[S:5][C:4]5[CH:30]=[CH:31][CH:32]=[CH:33][C:3]=5[C:2]=4[CH3:1])=[CH:8][N:9]=3)[S:13][C:14]=2[C:20]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:19][CH:18]=1
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3sc4ccccc4c3C)nc12
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3ncc(-c4sc5ccccc5c4C)[nH]3)nc12
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 0.16 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(3-methyl-benzo[b]thiophen-2-yl)-2-oxo-ethyl]-amide and 0.44 g ammonium triflouroacetate was melted at 180° C. for 45 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:1 gave 0.08 g (51%) 4-methoxy-2-[5-(3-methyl-benzo[b]thiophen-2-yl)-1H-imidazol-2-yl]-7-morpholin-4-yl-benzothiazole as yellow solid; M.p.: 213–215° C.; MS (ISP): m/e=463 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:11]([C@H:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)c1cc2cccc(F)c2nc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Temperature: -55 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
In a round bottomed flask was dissolved (+)-dip-chloride(tm) (17.5 g, 540 mmol, 2.2 eq) in anhydrous THF (200 mL) and the solution was cooled to −55° C. (using a dry ice/MeCN bath). To this solution was added 1-(2-chloro-8-fluoroquinolin-3-yl)ethanone (5.50 g, 24.5 mmol) as a solution in THF (50 mL). The reaction was allowed to warm to rt slowly overnight. After this time the reaction was quenched with 10 mL acetone and 100 mL of 10% Na2CO3 and allowed to stir for 2 h at rt. Ethyl acetate (750 mL) was added and the layers were separated. The organic phase was washed 3× with a 50% saturated sodium bicarbonate solution and once with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was concentrated under high vacuum at 75° C. to remove pinene. The residue was slurried in 150 mL of hexanes and 150 mL of water for 3 h at rt. A white precipitate formed and was filtered and dried to afford 4.9 g of 98% ee product. The solid was dissolved in 25 mL of boiling EtOAc and 25 mL of hot hexanes was added to form a precipitate at reflux. The mixture was cooled to −15° C., filtered, and washed with cold 9:1 hexanes:EtOAc to afford (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (4.07 g, 73% yield). Chiral HPLC (10% IPA in hexanes, chiralcel AD-H shows product to be >99.9% ee. Desired enantiomer elutes at 9.6 min, undesired enantiomer elutes at 8.1 min. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s), 7.64 (br d, J=8.2 Hz, 1H), 7.50 (td, J=7.8, 4.7 Hz, 1H), 7.41 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 5.40 (qd, J=5.9, 0.8 Hz, 1H), 2.22 (br s, 1H), 1.62 (d, J=6.3 Hz, 3H). Mass Spectrum (ESI) m/e=226.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a mixture of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5 g, 13.65 mmol) in CH2Cl2 (20 mL) was added Dess-MartinPeriodinane (6.37 g, 15.02 mmol) and the reaction mixture was stirred at room temp for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with saturated NaHCO3 solution (100 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by a quick silica gel chromatography to afford (3.8 g, 76%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.10-7.98 (m, 1H), 7.89 (td, J=4.4, 1.5 Hz, 1H), 7.51-7.36 (m, 2H), 7.00 (s, 1H), 4.00 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CS(=O)(=O)N1CCc2ccc(N)cc2CC1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(S(C)(=O)=O)CC3)ncc1Cl

Procedure:
5-Chloro-N*2*-(3-methanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 3-methanesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 318b. Product isolated as a pale yellow solid (60 mg, 37%). m.p.=204-206° C.; LCMS (m/e) 559 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.17 (d, 1H, J=8.8 Hz), 8.01 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.04 (d, 1H, J=7.9 Hz), 6.88 (s, 1H), 6.54 (s, 1H), 6.49 (d, 1H, J=9.0 Hz), 3.91 (s, 3H), 3.91-3.87 (m, 4H), 3.47-3.40 (m, 4H), 3.19-3.13 (m, 4H), 3.03-2.95 (m, 4H), 2.77 (s, 3H).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][Mg]Br)=[CH:36][CH:35]=1>C1COCC1>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:14][CH:15]=2)=[O:9])=[CH:36][CH:35]=1
Reactant: COc1ccc(C[Mg]Br)cc1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 29.4 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]-methanone (6.0 g, 13.7 mmol) in THF (51 mL) was reacted with a 0.83M THF solution of 4-methoxybenzylmagnesium bromide (19.8 mL, 16.4 mmol) (prepared from 4-methoxybenzylchloride and magnesium turnings in THF) at ambient temperature. Purification by chromatography (silica gel, 1:1 hexane:ethyl acetate, 0.1% ammonium hydroxide) and recrystallization from ethyl acetate gave 2.08 g (29%) of the title compound as tan crystals, mp 126° C.: 1H NMR (300 MHz) δ1.3-1.5 (m, 2H), 1.5-1.7 (m, 4H), 2.4-2.6 (br m, 4H), 2.77 (br m, 2H), 3.73 (s, 3H), 3.83 (s, 3H), 4.08 (s, 2H), 4.23 (br m, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.90 (dd, J=2.5, 8.8 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.9 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.80 (d, J=8.7 Hz, 2H); IR (CHCl3) 1645, 1600 cm-1 ; HRMS (FAB+) m/e calc'd for C31H34NO4S 516.2208 (MH+), found 516.2200; Anal. calc'd. for C31H33 NO4S.0.5H2O: C, 70.95; H, 6.54; N, 2.67. Found: C, 71.17; H, 6.51; N, 2.56.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:33]4[CH:38]=[N:37][C:36]([NH2:39])=[CH:35][CH:34]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3ccc(N)nc3)cc1-2
Yield: 13.3 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.5 mg, 0.128 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (33.7 mg, 0.153 mmol) were reacted to give 279 (7.2 mg, 13% yield, M+1 425.1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>>[N:10]1[CH:11]=[CH:12][C:7]([NH:3][CH2:2][CH2:1][NH2:4])=[CH:8][CH:9]=1
Reactant: Brc1ccncc1
Reactant: NCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCCNc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
Ethylenediamine (10.4 ml, 155 mmol) was added to 4-bromopyridine hydrochloride (3.00 g, 15.5 mmol) under a nitrogen atmosphere, and the mixture was refluxed for 1.5 hours. The temperature was cooled to room temperature, potassium carbonate (8.57 g, 62.0 mmol) was added to the reaction mixture, and the whole was stirred for 10 minutes. Then, the solid was filtered out and washed with toluene and 2-propanol successively. The filtrate was concentrated under reduced pressure, the residue was purified by basic silica gel column chromatography, and the resulting solid was filtered off with diisopropyl ether to give 1.63 g (77%) of the titled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24]>>[CH3:1][C:2]1[N:3]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: COCCOCCCl
Product: COCCOCCn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-chloro-2-{[2-(methyloxy)ethyl]oxy}ethane: MS (ES) m/z 327 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(N(CC)CC)C.CS(ON=C(C#N)C(OCC)=O)(=O)=O>CN(C)C=O.C(OCC)(=O)C.O>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:22](=[O:24])[C@H:12]([CH2:13][S:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](CSCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)[C@H](CSCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 14 h
Yield: 23.2 %

Procedure:
N-Benzyloxycarbonyl-S-benzyl-L-cysteine (1.73 g) and glycine ethyl ester hydrochloride (0.70 g) are dissolved in dimethylformamide (12 ml), and thereto are added triethylamine (1.40 ml) and further ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g). The mixture is allowed to stand at room temperature for 14 hours. To the reaction mixture are added water and ethyl acetate, and the ethyl acetate layer is separated, washed with water, 1 N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate and water in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the resulting residue is crystallized from ethanol-petroleum ether, separated by filtration and dried to give N-(N-benzyloxycarbonyl-S-benzyl-L-cysteinyl)glycine ethyl ester (0.5 g), melting point: 93°-95° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1ccc(Br)cc1)c1ccccc1
Yield: 38.2 %

Procedure:
A mixture of phenylacetone (4.92 g, 36.7 mmol) and 4-bromobenzaldehyde (6.78 g, 36.7 mmol) in benzene (40 ml) in the presence of piperidine (0.11 ml, 1.47 mmol) was refluxed for 48 hours. After evaporation, the obtained residue was chromatographed on a column of silica gel (300 g) as eluting with ethyl acetate/hexane (1:20 to 1:2) to afford a yellow solid, which was washed with ethyl acetate/hexane to give 4.22 g (38%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].[H-].[Na+].[CH3:23]I>CN(C=O)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OCc2ccccc2)ccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)ccc2c1ccn2C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
4-Allyl-5-(benzyloxy)-1H-indole (368.7 mg, 1.40 mmol) (Example 58) was dissolved in anhydrous DMF (12 mL) under an inert atmosphere, and the reaction mixture was cooled in an ice-water bath. Sodium hydride (60% in mineral oil) (181 mg, 1.68 mmol) was added, and the reaction mixture was stirred for an additional 30 min. Methyl iodide (278 mg, 1.96 mmol) was added and stirring at rt was continued for 30 min. The reaction mixture was heated to 40° C. for 12 h, cooled to rt, and water (10 drops) was added. The reaction mixture was concentrated under reduced pressure, after which water was added, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:15) gave 259 mg (67%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.72 (m, 5H), 4.98 (d, 1H), 5.07 (d, 1H), 5.12 (s, 2H), 6.06 (m, 1H), 6.47 (s, 1H), 7.00 (d, 1H), 7.03 (s, 1H), 7.12 (d, 1H), 7.31 (m, 1H), 7.39 (m, 2H), 7.48 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=3)[C:27]#[N:28])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 197-199° C.; 1H NMR (DMSO-d6): δ 10.09 (s, 1H), 8.25 (dd, J=6.35, 2.44 Hz, 1H), 8.02-8.05 (m, 1H), 7.68 (dd, J=8.3, 1.95 Hz, 1H), 7.61 (d, J=1.95 Hz, 1H), 7.7 (dd, JHF=9.28 Hz, JHH=9.28 Hz, 1H), 7.56 (dd, J=5.37, 1.47 Hz, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.0 (dd, J=4.88, 3.42 Hz, 1H), 6.95 (dd, J=3.9, 1.47 Hz, 1H), 4.08 (d, J=15.62 Hz, 1H), 3.94 (d, J=15.13 Hz, 1H), 2.46-2.57 (m, 2H), 0.76 (t, J=6.83 Hz, 3H); MS (ESI) m/z 393 ([M+H]+); MS (ESI) m/z 391 ([M−H]−); Anal. calcd for C22H17FN2O2S: C, 67.33; H, 4.37; N, 7.14. Found: C, 67.26; H, 4.38; N, 6.90.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O>[F:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(F)c1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cccc(F)c1C=O
Temperature: 70 °C

Procedure:
1.37 g (9.85 mmol) 2-amino-6-fluoro-benzaldehyde are combined with 20 ml acetic anhydride and heated to 70° C. for 4 h. Then the reaction mixture is stirred into 200 ml dist. water, adjusted to pH 7 with Na2CO3 and extracted three times with 50 ml of ethyl acetate. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (80:20).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH:15]1([CH2:18][NH:19][C:10](=[O:12])[CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: O=C(CC(=O)c1ccccc1)NCC1CC1
Temperature: 150 °C

Procedure:
Ethyl benzoylacetate (621 mg, 3.23 mmol) and cyclopropylmethylamine (0.34 ml, 3.92 mmol) were dissolved in 1,4-dioxane (1 ml). Para-toluenesulfonic acid (3 crystals, catalytic) was added and the mixture heated under microwave irradiation at 150° C. for 30 min. The crude mixture was poured onto a SiO2 column and purified by flash chromatography (eluted with EtOAc 10 to 35% in hexanes). The title compound was isolated as a yellow solid (309 mg, 44%). HPLC (4 minutes gradient) tR 2.04 min; MS m/z 218.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[I-].[Na+].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7])=[N+:14]=[N-:15]
Reactant: CNS(=O)(=O)CCCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-N-methylbutane-1-sulfonamide (Example 5; 180 mmol), and sodium iodide (198 mmol) in DMF (180 ml) was stirred for 10 min at room temperature. Sodium azide (397 mmol) was added and the reaction mixture was stirred overnight at 60° C. The mixture was filtered off The organic phase was extracted with AcOEt/water. The crude mixture was concentrated and was used without further purification in the next step.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCNC1
Product: N#Cc1ccc(N2CCCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and pyrrolidine.
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[NH:32][C:33](=[O:49])[CH2:34][CH:35]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:42][C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)([CH3:5])([CH3:4])[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:60]([O:67][CH2:68][C:69](=O)[CH2:70][CH2:71][CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:69]([CH2:68][O:67][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:70][CH2:71][CH2:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)=[CH:8][C:7]=1[NH:32][C:33](=[O:49])[CH2:34][CH:35]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=2[O:42][C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(CCCC1CCCCC1)COCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C=C(CCCC2CCCCC2)COCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 65.4 %

Procedure:
A suspension of 1.36 g (1.87 mmol) of [4-t-butyl-3-[2-(9H-xanthen-9-yl)acetamido]phenyl]methyltriphenylphosphonium bromide (prepared as described in Preparation 34) in 15 ml of tetrahydrofuran was ice-cooled, and 2.10 ml (2.10 mmol) of a 1.0M tetrahydrofuran solution of sodium hexamethyldisilazide were added dropwise thereto over the course of 3 minutes. After 35 minutes, a solution of 511 mg (1.86 mmol) of 1-benzyloxy-5-cyclohexyl-2-pentanone (prepared as described in Preparation 35) in 5 ml of tetrahydrofuran was added to the mixture. The resulting mixture was stirred for 10 minutes whilst ice-cooling, at room temperature for 35 minutes and finally at 50° C. for 4.5 hours. At the end of this time, the temperature of the reaction mixture was lowered to room temperature, and then a saturated aqueous solution of ammonium chloride was added, in order to stop the reaction. The reaction mixture was then diluted with ethyl acetate and the diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 100 g of silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 781 mg (yield 65%) of the title compound as a foam-like material.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7])[CH3:2].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CNC1CCCC1

Procedure:
Reaction of 3-amino-2,2-dimethyl-propionic acid ethyl ester with cyclopentanone, sodium acetate and sodium triacetoxyborohydride in DCM gave 3-Cyclopentylamino-2,2-dimethyl-propionic acid ethyl ester
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.O[C:11]1[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:13]=2[N:14]=[N:15][N:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][C:11]1[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:13]=2[N:14]=[N:15][N:16]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1cccc(F)c1
Product: NC(=O)c1cccc2c(NCc3cccc(F)c3)nnnc12

Procedure:
Compound 9 was prepared following general synthetic scheme 7 wherein (3-fluorophenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [298 (M+1)], 1H NMR (400 MHz, DMSO-d6): 9.39 (s, 1H), 9.32 (s, 1H), 8.55-8.50 (m, 2H), 8.05 (s, 1H), 7.99 (t, 1H), 7.41-7.35 (m, 1H), 7.26-7.23 (m, 2H), 7.11-7.09 (m, 1H), 4.93 (d, 2H).