Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)(=[O:3])[CH3:2].[CH3:36][Mg]Br.C(=O)(O)[O-].[Na+].O>ClCCl>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)([CH3:36])[CH3:2]
Reactant: CC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(2-acetylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 532, 77 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL) and cooled to −78° C. Methylmagnesium bromide (0.056 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added dropwise and the mixture was stirred for 30 minutes at −78° C. Additional methylmagnesium bromide (0.057 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added and the mixture was stirred for an additional 30 minutes at −78° C. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated), warmed to ambient temperature, poured into water and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 0:100 hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.12 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.15 (1H, dd, J=8.0, 1.1 Hz), 7.90 (1H, dd, J=7.9, 1.3 Hz), 7.84 (2H, d, J=8.7 Hz), 7.78 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=1.4 Hz), 7.64-7.60 (1H, m), 7.53 (1H, t, J=7.6 Hz), 7.48 (2H, d, J=8.7 Hz), 7.46-7.43 (1H, m), 7.35 (1H, td, J=7.5, 1.3 Hz), 7.17 (1H, dd, J=7.5, 1.1 Hz), 6.53 (1H, dd, J=2.3, 1.9 Hz), 5.77 (2H, s), 5.28 (1H, s), 1.37 (6H, s) ppm; high resolution mass spectrometry (ES+) m/z 476.2069 [(M+H)+; calculated for C29H26N5O2: 476.2081].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH:3]2[CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: COc1ccc2c(c1)C(CO)CN(C(=O)OC(C)(C)C)C2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)C(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step G (10.5 g; 36 mmol) is dissolved in 150 ml of dichloromethane and then triethylamine (8.5 ml) is added. The solution is cooled to 0° C. and methanesulphonyl choride (4.8 ml; 62 mmol) is added dropwise. The reaction mixture is stirred at ambient temperature for 2 hours and then poured into 150 ml of water. The solution is extracted with dichloromethane, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The title compound is purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH3:12].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH3:12]
Reactant: CCc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 72 %

Procedure:
N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 42 from 5-amino-4-ethyl-3-trifluoromethylisoxazole and benzenesulfonyl chloride in 72% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give white needles, m.p. 105°-106.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([NH:9]C2C(=O)C(=O)C=2NC(C2OC(C)=CC=2)C2(C)COC2)=[CH:4][CH:3]=1.ClC1NC(=O)C([N+]([O-])=O)=CC=1>>[NH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C(Nc2c(Nc3ccc(Cl)nc3O)c(=O)c2=O)C2(C)COC2)o1
Agent: O=c1[nH]c(Cl)ccc1[N+](=O)[O-]
Product: Nc1ccc(Cl)[nH]c1=O

Procedure:
In a manner analogous to EXAMPLE 1 (steps 1 to 3, 6 and 7), 3-(6-chloro-2-hydroxypyridin-3-ylamino)-4-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione was prepared from 6-chloro-3-nitro-1H-pyridin-2-one. HPLC 94.8%, ES− [402].
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCCC1)c1ccncc1
Yield: 97 %

Procedure:
Isonicotinoyl chloride hydrochloride (704 mg, 3.95 mmol, commercially available product) and triethylamine (823 μl, 5.94 mmol) were sequentially added at 0° C. to a dichloromethane (6 ml) solution of 1-[2-amino-4-(trifluoromethyl)phenyl]-hexahydro-1H-azepine (512 mg, 1.98 mmol), obtained as described in Referential Example 4-2. The resulting mixture was stirred for one and a half hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=2/1). Thus, N-[2-(1-hexahydro-1H-azepinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0618) (697 mg, 97.0%) was yielded as a colorless solid.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:58])[CH2:38][C:39]1([CH2:42][CH2:43][CH:44]([CH:56]=O)[CH2:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)[CH3:35].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:34]([O:36][C:37](=[O:58])[CH2:38][C:39]1([CH2:42][CH2:43][CH:44](/[CH:56]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)[CH3:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC1(CCC(C=O)Cc2ccc(C(=O)OC)cc2)CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)CC1
Reaction time: 0.75 h

Procedure:
At 0° C., 4.11 ml (10.26 mmol) of a 2.5 M solution of n-butyllithium in hexane are added slowly to a solution of 2.471 g (5.5 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 25 ml of anhydrous THF, and the mixture is stirred for 45 min. At this temperature, 1.27 g (3.67 mmol) of methyl 4-{4-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-2-formylbutyl}benzoate are then metered in slowly, and the mixture is stirred at 0° C. for two hours. After complete conversion, saturated ammonium chloride solution is added, and the reaction solution is concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is evaporated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 757 mg (47% of theory) of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)=[N:22][N:21]=[C:20]1[CH2:36][N:37]([CH3:39])[CH3:38].O.NN>C(O)C>[F:18][C:15]([F:17])([F:16])[C:13]1[CH:12]=[CH:11][C:10]2[N:19]3[C:20]([CH2:36][N:37]([CH3:39])[CH3:38])=[N:21][N:22]=[C:23]3[CH2:24][N:25]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 27, 2'-chloro-5(trifluoromethyl)-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4](/[CH:7]=[C:8](/[C@H:10]2[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[C:23]([CH3:31])([CH3:30])[C:21](=[O:22])[C@H:20]([CH3:32])[C@@H:19]([OH:33])[C@@H:18]([CH3:34])[CH2:17][CH2:16][CH2:15][C@H:13]3[O:14][C@H:12]3[CH2:11]2)\[CH3:9])[N:3]=1.C[OH:36]>>[CH3:34][C@@H:18]1[C@H:19]([OH:33])[C@@H:20]([CH3:32])[C:21](=[O:22])[C:23]([CH3:31])([CH3:30])[C@@H:24]([OH:29])[CH2:25][C:26](=[O:27])[O:28][C@H:10](/[C:8](/[CH3:9])=[CH:7]/[C:4]2[N:3]=[C:2]([CH2:1][OH:36])[S:6][CH:5]=2)[CH2:11][C@@H:12]2[O:14][C@@H:13]2[CH2:15][CH2:16][CH2:17]1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: CO
Product: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reaction time: 21.5 h

Procedure:
The concentrated culture is transferred to a 4 liter bioreactor and a methanolic solution of 1 g of epothilone A in 10 ml of methanol is added. The culture is then cultured further for a period of time of 21.5 h. The temperature is 32° C., the stirrer speed is 455 rpm and the introduction of air takes place at 6 l/min. At the time of harvesting, 100 ml of XAD is added and the mixture is incubated further for 1 h. The XAD is separated from the cells by screening and exhaustively eluted with methanol. The concentrated eluate is analysed by means of HPLC.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8][C:9]1[CH:22]=[CH:21][C:20]2[O:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:23][OH:24])[CH:17]=3)[CH2:12][C:11]=2[CH:10]=1.C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O.C(OCC)(=O)C>[CH3:7][S:8][C:9]1[CH:22]=[CH:21][C:20]2[O:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:23]=[O:24])[CH:17]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: CSc1ccc2c(c1)Cc1ccc(CO)cc1O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CSc1ccc2c(c1)Cc1ccc(C=O)cc1O2
Temperature: 25 °C

Procedure:
Under dry nitrogen, dimethylsulphoxide (5 ml) was added dropwise to a stirred solution of oxalyl chloride (0.89 ml) in methylene chloride (5 ml) at -60° C. After 2 minutes a solution of the xanthene from step (A) (2.3 g) in dimethylsulphoxide (35 ml) was introduced dropwise over 5 minutes whilst maintaining the temperature below -50° C. with cooling. After 15 minutes triethylamine (6.20 ml) was added, the mixture allowed to warm to room temperature and then poured into water. The mixture was ethyl acetate extracted, the organic layers were combined, washed with brine, dried over magnesium sulphate and evaporated yielding the title carboxaldehyde (1.97 g), m.p. 122°-123° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7][NH:8][C:9](=[O:17])[CH:10](OCC)COC)=[CH:4][S:5][CH:6]=1.Br>C(O)(=O)C>[Br:1][C:2]1[C:3]2=[CH:7][NH:8][C:9](=[O:17])[CH:10]=[C:4]2[S:5][CH:6]=1
Reactant: CCOC(COC)C(=O)NCc1cscc1Br
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc2scc(Br)c2c[nH]1
Yield: 45.2 %

Procedure:
A solution of N-[(4-bromothiophen-3-yl)methyl]-2-ethoxy-3-methoxypropanamide (729 mg, 2.26 mmol) in acetic acid (4.5 mL) and hydrogen bromide (2.2 mL, 41 mmol) was heated to reflux for 2 h. Upon cooling a precipitate formed. The precipitate was collected by vacuum filtration, washing with acetic acid (2×10 mL) and diethyl ether (2×10 mL). The collected solid was suspended in water (10 mL) and treated with solid sodium bicarbonate until the solution pH was −8. The solid was then collected by vacuum filtration, washing with water (2×10 mL). The collected solid was dried in an oven at 50° C. for 16 h to afford 235 mg (45%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.82 (br. s., 1 H), 8.07 (s, 1 H), 7.55 (s, 1 H), 7.01 (s, 1H); MS (ESI): 230.01, 231.99 [M+H]+; HPLC tR=2.53 min (ZQ3, polar—4 min).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:11]([O:14][CH3:15])(=[O:13])[CH3:12].[C:16]([O:20][C:21]([N:23]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:24]1[CH:25]=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:24]1[CH:25]([OH:26])[CH2:12][C:11]([O:14][CH3:15])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CC(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To tetrahydrofuran (5 ml) were successively dropwise added a 1.0M sodium hexamethyldisilazide--tetrahydrofuran solution (0.910 ml, 0.910 mmol) and methyl acetate (72.0 μl) at -78° C. The mixture was stirred for 30 minutes, and a tetrahydrofuran solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (200 mg, 0.607 mmol) was added thereto at the same temperature. This solution was stirred for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (heptane-ethyl acetate=3:1) to give the title compound [232 mg, yield: 94.7%; (R)-isomer (polar compound):(S)-isomer (less polar compound)=6.27:1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:37]I>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:31]([F:33])([F:32])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([N:20]([CH3:37])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)Cc1ccccn1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
In a solution of 0.35 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-234) synthesized similarly to Synthetic Example 5 in 20 ml of N,N-dimethylformamide, 0.04 g of 55% oily sodium hydride was added under cooling with ice with stirring, and stirred at the same temperature for 30 minutes. Then, 0.12 g of methyl iodide was added and thereafter the temperature was raised to room temperature, and continued to stir at the same temperature for further 2 hours. After the completion of the reaction, the reaction mixture was diluted with 80 ml of ethyl acetate, washed with water (50 ml×2), dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with high performance liquid chromatography that was eluated with acetonitrile-water (85:15) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:24][CH3:25])[CH:8]=[C:9]([CH2:12][C:13](=[CH:16]NC3C=CC=CC=3)[C:14]#[N:15])[CH:10]=2)[O:5][C:4]([CH3:27])([CH3:26])[CH:3]=1.Cl.[NH2:29][C:30]([NH2:32])=[NH:31].CC(C)([O-])C.[K+]>C(O)C>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:24][CH3:25])[CH:8]=[C:9]([CH2:12][C:13]3[C:14]([NH2:15])=[N:31][C:30]([NH2:32])=[N:29][CH:16]=3)[CH:10]=2)[O:5][C:4]([CH3:27])([CH3:26])[CH:3]=1
Reactant: COc1cc(CC(C#N)=CNc2ccccc2)cc2c1OC(C)(C)C=C2Br
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc2c1OC(C)(C)C=C2Br
Yield: 48.4 %

Procedure:
The above prepared 418 mg of 2-(4-bromo-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrile were treated with 248 mg of guanidine hydrochloride (3.3 eq.), 291 mg of potassium-t-butoxide (3.3 eq.) and 16 ml of ethanol and heated under reflux under argon atmosphere for 14 hours. After cooling, the reaction mixture was poured onto crushed ice, extracted twice with AcOEt, washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2 with CH2Cl2/MeOH/25% NH3=19/1/0.05), followed by crystallization from EtOEt afforded 186 mg of the title compound as light-yellow crystals, mp.238-239°.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[S:6][C:5](=[N:7][CH2:8][CH3:9])[S:4][C:3]1=[N:10][OH:11].[CH3:13][N:14]([S:18][C:19]([Cl:22])([Cl:21])[Cl:20])[C:15](F)=[O:16]>O1CCOCC1.O>[CH3:12][C:2]1([CH3:1])[S:6][C:5](=[N:7][CH2:8][CH3:9])[S:4][C:3]1=[N:10][O:11][C:15](=[O:16])[N:14]([CH3:13])[S:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: CCN=C1SC(=NO)C(C)(C)S1
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Solvent: O
Solvent: C1COCCO1
Product: CCN=C1SC(=NOC(=O)N(C)SC(Cl)(Cl)Cl)C(C)(C)S1
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a solution of 3.5 grams (0.017m) of 5,5-dimethyl-2-ethylimino-4-oximino-1,3-dithiolane (XXIII) and 3.84 grams (0.017m) of N-methyl-N-trichloromethanesulfenyl carbamoyl fluoride in 75 ml of dioxane, was added dropwise with stirring 1.71 grams (0.017m) of triethylamine. After allowing the reaction mixture to stand at room temperature for 16 hours it was diluted with 250 ml of cold water and was extracted in ethylacetate. The organic extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to a residual oil which crystallized on the addition of isopropyl ether and hexane, to afford 4.0 grams of a white solid. m.p. 69°-71° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1ccccc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and N-methylaniline, the title compound was isolated as a yellow solid in 75% yield (99% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=O)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[CH2:39][NH2:40].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[CH2:39][NH:40][CH2:26][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:28])[C:16]2[O:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: COc1ccc(CN)c(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cc(-c3c(C)noc3C)c3c4c2[nH]c(=O)n4[C@@H](c2ccccn2)CO3)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
A solution (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (250 mg, 0.664 mmol) in ethanol (12.5 mL) was treated with 1-(2,4-dimethoxyphenyl)methanamine [Aldrich #: 432725](150 μL, 0.996 mmol) and acetic acid (20.0 μL, 0.352 mmol) and heated at 60° C. for 1 h. The reaction mixture was cooled to room temperature, treated with sodium cyanoborohydride (210 mg, 3.3 mmol) and stirred at room temperature for 3 h. The reaction mixture was then quenched with acetic acid (1 mL) and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the desired product (0.40 g, 97%) as a single enantiomer which was used without further purification. LCMS calculated for C29H30N5O5 (M+H)+: m/z=528.2. found: 528.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:6]=2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[S-2].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:20])[C:7]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: COc1ccc2c(c1)C(=O)N(C)CC(CCCl)O2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Agent: [S-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=S)N(C)CC(CCCl)O2
Yield: 86.3 %

Procedure:
To a solution of 10.3 g (0.04 mole) of 2-(2-chloroethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5(4H)-one in 200 ml of chloroform was added a mixture of 5.7 g (0.03 mole) of phosphorus pentasulfide and 5.7 g of potassium sulfide which had been ground together. The reaction mixture was stirred and heated at reflux under nitrogen atmosphere for 5 hr. The mixture was filtered hot and the filtrate concentrated under reduced pressure. The residue, an orange solid, was recrystallized from ethanol to give 7.4 g (65%) of product, m.p. 98°-100° C.