Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[O:17][N:16]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:9][CH2:8]1)(=O)=O.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][CH:18]([C:15]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][O:5][C:34]3[CH:33]=[CH:32][C:31]([C:28]4[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[CH:26][CH:27]=4)=[N:36][CH:35]=3)[CH2:12][CH2:11]2)[O:17][N:16]=1)[CH3:19]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (82.3 g, 271 mmol), 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (71.0 g, 285 mmol), powdered potassium carbonate (118 g, 855 mmol) and N,N-dimethylformamide (750 mL) was mechanically stirred and heated at 80° C. under nitrogen for 20 h. The reaction was cooled to ambient temperature, poured onto ice water (3 L) and allowed to stand for 1 h. The resulting solid was filtered, rinsed with water (2×500 mL) and air-dried. The solid was taken up in dichloromethane (300 mL) and methanol (500 mL). The dichloromethane was slowly removed via rotovap at 55° C. The methanol solution was allowed to stand at ambient temperature for 16 h. The resulting crystalline solid was filtered, rinsed with cold methanol and dried under vacuum at 60° C. for 18 h to afford the desired product (105.7 g, 84%) as a light tan solid. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.8 Hz), 8.13 (d, 2H, J=8.6 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, Ja=8.7 Hz, Jb=3.0 Hz), 4.24 (d, 2H, J=13.1 Hz), 3.95 (d, 2H, J=6.2 Hz), 3.17-3.04 (m, 5H), 2.94-2.84 (m, 1H), 2.11 (bs, 1H), 1.97 (d, 2H, J=12.6 Hz), 1.54-1.42 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 457 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH3:13][SH:14].[Na]>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:14][CH3:13]
Reactant: CS
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Na]
Solvent: CO
Product: CSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 ml solution of 50 g (0.262 mol) of 2-chloro-2',4'-difluoroacetophenone [Compound (4)-1] in methanol, 147 g (0.314 mol) of a 15% aqueous solution of sodium methylmercaptan were added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. Water was then added to the reaction mixture and they were mixed. The resulting mixture was extracted with chloroform. The extract was washed successively with water and saturated saline and then, dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The oil so obtained was distilled under reduced pressure (93-95° C., 3 mmHg), whereby 47.3 g of the title Compound (2a-1) were obtained as a colorless oil (yield: 89.2%).
Reaction SMILES: [N:1]1([C:7]2([C:13](N)=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na]>C(O)CC.CCCCCC>[N:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C1(N2CCCCC2)CCNCC1
Agent: [Na]
Solvent: CCCO
Solvent: CCCCCC
Product: OCC1(N2CCCCC2)CCNCC1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In a three neck round-bottom flask equipped with a stirring bar, reflux condenser, and rubber septa is placed [1,4′]bipiperidinyl-4′-carboxylic acid amide (5.01 g, 23.7 mmol) in 140 mL of anhydrous 1-propanol and the solution is heated to reflux. Sodium metal (˜9.276 g, 403.4 mmol) rinsed in hexane to remove mineral oil) is added in portions. Once the sodium metal completely dissolves, the mixture is allowed to stir over the weekend. The reaction mixture is cooled to room temperature and the solvent removed under reduced pressure. Distilled water is added and the solution extracted with chloroform. The organic layer is collected, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to afford 4.4 g of the desired product which is used without further purification. 1H NMR (CD3OD, 300 MHz) δ 1.48–1.60 (m, 8H), 1.72–1.80 (m, 2H), 2.61–2.71 (m, 6H), 2.92–3.01 (m, 2H), 3.37 (s, 1H), 3.56 (s, 2H). MS (ESI) m/z 199 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2].[F:25][C:26]1[C:31]([OH:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19]([O:32][C:31]4[C:30]([F:33])=[C:29]([F:34])[C:28]([F:35])=[C:27]([F:36])[C:26]=4[F:25])(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (220 mg, 0.603 mmol) in DCM (5 mL) was added pentafluorophenol (110 mg, 0.603 mmol) at 0° C. Triethylamine (0.12 mL, 0.904 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM (3 mL) and concentrated under reduced pressure. The crude mass thus obtained was purified by column chromatography (12 g column; elution: 5% ethyl acetate in hexane) to get perfluorophenyl 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (180 mg, 58.4%) as a clear liquid. m/z (ESI) 512.0 (M+H)+.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[CH:51]=[CH:50][C:44]([CH2:45][S:46](Cl)(=[O:48])=[O:47])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:51]=[CH:50][C:44]([CH2:45][S:46]([N:37]2[CH2:38][CH2:39][N:34]([C:26]3[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[F:24])[CH2:35][CH2:36]2)(=[O:48])=[O:47])=[CH:43][CH:42]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(S(=O)(=O)Cc3ccc(Cl)cc3)CC2)cc1F
Yield: 100.6 %

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and 4-chlorobenzylsulfonyl chloride (338 mg), respectively, to provide crude 1-(4-chlorobenzylsulfonyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (419 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]([OH:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:18]I>O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:18])[CH:5]=[C:4]([CH:9]([OH:11])[CH3:10])[N:3]=1
Reactant: II
Reactant: CC(O)c1ccc(O)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(O)c1cc(I)c(O)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)-pyridine (4.5 g, 23.6 mmole) is suspended in 70 ml water in a 200 ml one neck round bottom flask. The suspension is treated successively with potassium carbonate (6.5 g, 47.2 mmole) and iodine (12.0 g, 47.2 mmole) and the reaction mixture is stirred 4 h at room temperature. The excess iodine is quenched with saturated sodium thiosulfate and the pH of the reaction mixture is adjusted to 3 with 10% hydrochloric acid. The solid is collected, washed with water, and is taken up in ethyl acetate. The organic layer is dried over magnesium sulfate and is concentrated in vacuo to a yellow solid. The solid is washed with chloroform and is dried to provide 4.4 g (62%) of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:16]([N:19](C(C)C)CC)(C)[CH3:17].BrCC#N.[I-].[Na+].FC(F)(F)C(O)=O.[Cl-].[NH4+]>CN1C(=O)CCC1.CC#N.O>[C:16]([CH2:17][N:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:19]
Reactant: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN(CC#N)c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
Ethyl N-(3,4-dichlorophenyl)glycinate (4.0 g, 16.1 mmol), diisopropylethylamine (3.37 mL, 19.3 mmol), bromoacetonitrile (1.23 mL, 17.7 mmol) and sodium iodide (2.41 g, 16.1 mmol) were dissolved in 25 mL of dry NMP and heated to 120° C. After 20 h, HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that approximately half of the starting material (Rt=7.8 min) was consumed and that a new peak had formed (Rt=7.6 min). The reaction was monitored periodically by HPLC and additional bromoacetonitrile was added as needed to achieve complete conversion. In this case, an additional 1.5 equivalents (1.68 mL, 24.1 mmol) of bromoacetonitrile was added and the reaction was heated for an additional 28 h, after which time the HPLC indicated that the reaction was complete. The reaction mixture was poured into 400 mL of 50% saturated ammonium chloride and extracted with 500 mL of ethyl acetate. The layers were separated and the organic layer was washed with 50% saturated sodium bicarbonate (400 mL), water (400 mL), and saturated NaCl (400 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to a black oil which was adsorbed onto approximately 15 g of silica gel. The crude residue was purified by column chromatography (300 g silica gel 40 um, gradient elution from 30-70-100% EtOAc/hexanes over 40 minutes) to give the title compound as a yellow solid (2.59 g, 9.02 mmol, 56%). LC/MS (APCI) m/e 260 [M−CN]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[CH:33][CH:32]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-morpholinoaniline (69 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 44% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.41 (1H, m), 9.00 (2H, s), 8.67 (1H, s), 7.51 (2H, m), 6.94 (2H, m), 3.72 (4H, m), 3.06 (4H, m). MS m/z: 509.15, 511.13 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7]1[N:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[N:12]=1)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:9]1[C:10]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[N:12]=[C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])[N:8]=1
Reactant: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of the product of Example 83 (20 mg, 0.43 mmol) in THF (2 mL) was added LiOH (40 mg, 1.67 mmol) dissolved in H2O (1 mL). The reaction mixture was stirred 1 h at 23° and then neutralized with 1 M HCl, extracted with EtOAc (5 mL) and the layers were separated. The organic layer was washed with H2O, satd. aq NaCl, and dried (MgSO4). The solution was filtered and evaporated to give the title compound [4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid. LC MS (m/e)=441 (MH+). Rt=1.85 min
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C([Li])CCC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC.C(=O)(O)[O-].[Na+]>[C:23]([N:9]1[C@H:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]1=[O:17])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 101.7 %

Procedure:
To a solution of 2.35 g (10 mmol) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one in 40 mL of THF at -78° C. was added 6.1 mL (10.07 mmol) of a 1.65M solution of n-butyllithium in hexane. The mixture was stirred for 10 min at -78° C. and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78° C. for 1 h and diluted with 70 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to give 3.45 g of an oil. Chromatography of the oil on silica gel eluted with ethyl acetate/hexane gave 3.22 g (95%) of cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (2) as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH3:24])[CH2:22]OS1(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH4+].[Cl-]>CN(C=O)C>[C:12]([O:16][C:17](=[O:18])[NH:19][C@@H:23]([CH3:22])[CH2:24][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: Oc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
β-Naphthol (721 mg) was dissolved in DMF (25 mL) and cooled to 0° C. Potassium-tert-butylate (1M in THF, 6.0 mL) was added drop by drop over a periode of 15 minutes and the mixture was stirred for 30 min. (S)-4-Methyl-2,2-dioxo-[[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (IV, 1.42 g) was added in one portion and stirring was continued for 3 hours. The reaction mixture was poured into 1M NH4Cl and extracted with ether. The organic phase was washed with 1M NH4Cl and brine, dried over Na2SO4 and evaporated to yield a yellow solid. The crude product was purified by flash chromatography (ethyl acetate/hexanes 1:9) to give the desired product as a colorless solid (1.5 g).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10]Br)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][O:20][Si](C(C)(C)C)(C)C)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)([O-:33])=[O:32].CN1CCOCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:28]([C:6]1[C:7]([CH2:19][OH:20])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9]([CH2:10][S:40][C:37]2[CH:38]=[CH:39][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)([CH3:29])[CH3:30]
Reactant: CC(C)c1nc(C(C)C)c(CO[Si](C)(C)C(C)(C)C)c(-c2ccc(F)cc2)c1CBr
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)c1nc(C(C)C)c(CSc2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C

Procedure:
The intermediate obtained in Step B (200 mg, 0.40 mmol) was dissolved in anhydrous THF (5 mL), stirred under argon at room temperature and treated with 4-nitrothiophenol (118 mg, 0.6 mmol, 80% tech. grade) and N-methylmorpholine (0.2 mL, 1.8 mmol). The reaction mixture was allowed to stir at reflux for 18 hr, then cooled to room temperature. The mixture was treated with tetrabutylammonium fluoride (0.8 mL, 0.8 mmol, 1.0M in THF) and allowed to stir at room temperature for 24 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (100 mL), washed with 1N HCl (50 mL), sat. NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated. Purification by chromatography through silica (step gradient 5-10% ethyl acetate/hexane) afforded the title compound as a lightly colored solid (130 mg, 0.28 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J=8.5 Hz, 2 H), 7.27 (m, 2 H), 7.13 (m, 4 H), 4.37 (d, J=5.5 Hz, 2 H), 3.91 (s, 2 H), 3.46 (sept, J=6.6 Hz, 1 H), 3.33 (sept, J=6.6 Hz, 1 H), 1.35 (d, J=6.6 Hz, 6 H), 1.34 (d, J=6.6 Hz, 6 H), 1.27 (t, J=5 Hz, 1 H). FAB-MS calcd for (C25H27FSN2O3) 454, found 455 (M+H). mp 178-180° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)CCCC(C)(C)N1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][N:12]([CH2:13][CH2:14][CH:15]([OH:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:9]=1
Reactant: CNCCC(O)c1ccccc1
Reactant: Fc1ccc(Cl)cc1CBr
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: CN(CCC(O)c1ccccc1)Cc1cc(Cl)ccc1F
Yield: 73.2 %

Procedure:
A solution of 5-chloro-2-fluorobenzyl bromide (10.5 g) in acetonitrile (100 ml) was added dropwise to a mixture of N-methyl-3-hydroxy-3-phenylpropylamine (7.7 g), 2,2,6,6-tetramethylpiperidine (8 ml) and acetonitrile (100 ml) After 12 h the mixture was filtered, the filtrate evaporated and the residue chromatographed on silica (Woelm Grade 1) using ether as eluant to give the title compound as an oil (10.5 g), b.p. 160°/0.5 mm.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[O:7][N:6]=4)=[C:12]3[CH2:13][N:14]([CH3:24])[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: C1CCNC1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCC4)n3)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 82.1 %

Procedure:
A suspension of 1.50 g (0.0043 mol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl) -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepin-6-one in 15 ml of dimethylformamide was treated with 1.5 g (0.022 mol) of pyrrolidine. After stirring at room temperature for 65 hrs. the yellow-orange solution obtained was freed completely from solvent. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. The product was recrystallized from methanol/ether. There were obtained 1.35 g (82%) of 8-fluoro-5-methyl-3-(5-pyrrolidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 158°-160°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH:32]([CH3:33])[CH3:34])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K39) (255 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light red solid (220 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=1)(=[O:31])=[O:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (3.83 g, 0.0153 mol; Icagen) was dissolved in THF (70 mL, 0.8 mol) and cooled in an ice bath. 1.0 M of Lithium hexamethyldisilazide in THF (33 mL) was added dropwise to the reaction. After 30 minutes, a solution of 4-(chlorosulfonyl)benzoic acid (3.07 g, 0.0139 mol) in THF (30 mL, 0.4 mol) was added dropwise to the reaction. The reaction was stirred overnight then quenched with 0.5 N HCl and diluted with ethyl acetate. The phases were separated and the organic phase was washed with 2× with 0.5N HCl. The organic phase was dried over magnesium sulfate, treated with activated carbon and filtered through Celite. The filtrate was evaporated to a residue and triturated with ethyl acetate. The solid was collected by filtration. Vacuum drying afforded the product as a tan solid (2.55 g, 40%).
Reaction SMILES: C(OC(N1C(C(O)C(O)C)CNC2NC(N=CN(C)C)=NC(=O)C1=2)=O)(C)(C)C.[C:29]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=[O:39])([O:31]C(C)(C)C)=[O:30]>>[N:36]1([C:29]([OH:31])=[O:30])[CH2:43][CH2:42][CH2:41][CH:37]1[C:38]([OH:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(O)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Product: O=C(O)C1CCCN1C(=O)O
Yield: 321.1 %

Procedure:
The product of Example 5, step b) was treated by the same method as that described in Example 10, step a) except N-Boc-L-Proline (12.6 g, 5.87 mmol) was used to give the sub-title compound as a pale yellow solid (3.0 g, 60%). MS: ESI (positive): 791 (M+H).