Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=[O:10])[C:3]=1[Cl:12].[OH-:13].[K+].O>C(O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2=[N+:6]([O-:13])[O:10][N:9]=[C:4]2[C:3]=1[Cl:12]
Reactant: [OH-]
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: [O-][n+]1onc2c(Cl)c(Br)ccc21
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
4-Bromo-3-chloro-2-nitroaniline (4.1 g, 16 mmol) was dissolved in 60 mL ethanol, treated with 45% potassium hydroxide solution (2.0 g, 16 mmol), cooled to −5 to 0° C. and treated drop wise with commercial bleach solution (32 mL, 6 wt. %, 31 mmol) over 20 min. The mixture was stirred for 90 min at 0-15° C. and poured into 700 mL water. The precipitated product was collected by filtration, washed well with water and then dried under vacuum at 80° C. to give the title compound (3.2 g, 81%): EIMS m/z 248.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:26]([C:23]1[CH:24]=[CH:25][O:21][CH:22]=1)=[O:27]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1ccoc1
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1ccoc1
Yield: 35 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with 3-furoyl chloride in 35% yield.
Reaction SMILES: [C:1]([O:9][CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C@H:12](CO)[CH:13]([CH3:15])[CH3:14]>[Zn].ClC1C=CC=CC=1>[CH:13]([C@H:12]1[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11]1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: [Zn]
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccccc2)=N1
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, a mixture of methyl benzoate (1.5 mmol), (S)-valinol (1.8 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.0375 mmol), and chlorobenzene (2.5 ml) was refluxed for 12 hours. As a result, (S)-4-isopropyl-2-phenyloxazoline was obtained in a yield of 84%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([SH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([S:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.7 %

Procedure:
To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-mercapto-3-methylbutanoic acid (4.5 g, 18.05 mmol) in THF (60 mL) was added a solution of methyl 2-bromoacetate (3.04 g, 19.85 mmol) in THF (10 mL) followed by DIPEA (9.46 mL, 54.1 mmol). The resulting mixture was stirred at rt for 4.5 h. The reaction mixture was concentrated in vacuo to remove most of the solvent, and the residue was diluted with EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was acidified with 1N HCl solution to adjust the pH to 2-3. The resulting aqueous layer was extracted with EtOAc (2×). The organic layers were combined and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as solid (4.8 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=9.0 Hz, 1H), 4.10 (d, J=9.5 Hz, 1H), 3.62 (s, 3H), 3.41 (s, 2H), 1.39 (s, 9H), 1.33 (s, 3H), 1.27 (s, 3H); MS (ESI+) m/z 266.0 (M-55)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29](O)(=[O:33])[C@H:30]([CH3:32])[OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[OH:31][C@@H:30]([CH3:32])[C:29]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:33]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)[C@H](C)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 4 h

Procedure:
A solution of 3.86 g of cholesterol and 0.85 ml of L-(+)-lactic acid (90% in water) in 80 ml of toluene is boiled for 1 hour. The water is separated, the cooled reaction mixture is treated with 0.3 g of p-toluene-sulphonic acid and boiled for a further 4 hours. The reaction mixture is treated with 30 ml of water and extracted with ether. The organic phase is dried over sodium sulphate and concentrated. The residue is purified on silica gel, with petroleum ether/ether 4:1 used as the elution agent. There are obtained 1.5 g of cholest-5-en-3β-yl (S)-2-hydroxypropionate, m.p. 120°-122° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:17])[C@H:4]1[C@H:8]([CH2:9][O:10][CH3:11])[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>CCOCC>[CH3:11][O:10][CH2:9][C@@H:8]1[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5][C@H:4]1[C:3]([Cl:17])=[N:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
(2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135.0 mmol) was dissolved in Et2O (600 mL) and cooled in an ice bath. Methanesulfonyl chloride (10.49 ml, 135.0 mmol) was added, followed by dropwise addition of triethylamine (18.82 ml, 135.0 mmol). The reaction was stirred for 30 minutes and then filtered and concentrated. The residue was purified on 1 Kg SiO2 (1 to 5% EtOAc in CH2Cl2) to afford (2R,3S)-3-(methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (22.6 g, 66.12 mmol, 48.98% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.Cl.Cl[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.O>[CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[N:30]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4n3CCN3CCOCC3)CC2)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide (0.70 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (0.84 mmol), and potassium carbonate (3.36 mmol) in acetone (10 mL), water (4 mL), and dichloromethane (5 mL). Heat to reflux. After 20 hours, cool to ambient temperature and concentrate the reaction mixture invacuo and dilute with ethyl acetate. Extract with saturated aqueous ammonium chloride solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over MgSO., filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C:12]1[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][N:17]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:21]([NH:11][C:12]1[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][N:17]=1)(=[O:23])[CH3:22]
Reactant: Nc1nccnc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1C(N)=O
Product: CC(=O)Nc1nccnc1C(=O)O
Yield: 76 %

Procedure:
A mixture of 3-aminopyrazine-2carboxylic acid o-toluamide (1.0 g, 4.39 mmol) and acetic anhydride (12 mL) was refluxed 2 hours. The solvent was removed and the residue was triturated with hot ethyl acetate. The ethyl acetate slurry was cooled and the product was collected and rinsed with ether to afford 0.893 g (76%) of 3-acetamidopyrazine-2-carboxylic acid o-toluamide.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[C:6]2[C@H:7]([CH2:13][Cl:14])[CH2:8][N:9](N)[C:10]=2[CH:11]=1.[CH3:19][S:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2)=[O:25].C(Cl)CCl>CC(N(C)C)=O>[Cl:14][CH2:13][C@H:7]1[C:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3]([OH:2])=[CH:11][C:10]=2[N:9]([C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([NH:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][S:20][CH3:19])=[CH:35][CH:34]=3)=[O:37])[CH2:8]1
Reactant: NN1C[C@@H](CCl)c2c1cc(O)c1ccccc21
Reactant: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)N3C[C@@H](CCl)c4c3cc(O)c3ccccc43)cc2c1

Procedure:
To a solution of 5-hydroxy-3-amino-1-[S]-(chloromethyl)-1,2-dihydro-3H-benz(e)indole, hydrochloride salt (155 mg, 0.57 mmol) and 5-(3-(methyl-disulfanyl)propanamido)-1H-indole-2-carboxylic acid (170 mg, 0.55 mmol) in 7.0 ml of DMA was added EDC (300 mg, 1.56 mmol) under Ar. After stirred over night, the mixture was evaporated to dryness, purified by SiO2 chromatography (20% to 40% THF in toluene) and crystallized with THF/Toluene/Hexane to afford 218 mg (76%) of DC101SMe. 1H NMR (DMF-d7) 11.63 (s, 1H), 10.56 (s, 1H), 9.95 (s, 1H), 8.23 (s, 2H), 7.93 (d, 1H, J=8.3 Hz), 7.56 (dd, 1H, J=2.0, 8.1 Hz), 7.52 (s, 1H), 7.47 (dd, 1H, J=1.9, 8.9 Hz), 7.41 (d, 1H, J=1.7 Hz), 7.25 (d, 1H, J=1.7 Hz), 4.88 (dd, 1H, J=8.7, 11.0 Hz), 4.73 (dd, 1H, J=2.3, 10.9 Hz), 4.31 (m, 1H), 4.12 (dd, 1H, J=3.1, 11.0 Hz), 3.95 (dd, 1H, J=8.4, 11.2 Hz), 3.21 (t, 2H, J=7.1 Hz), 2.71 (t, 2H, J=7.1 Hz), 2.45 (s, 3H); 13C NMR 169.54, 161.06, 155.36, 134.21, 133.39, 132.54, 131.05, 128.39, 127.99, 123.98, 123.74, 123.46, 123.31, 118.88, 115.99, 112.87, 112.31, 106.40, 101.33, 55.93, 48.10, 42.61, 36.92, 30.81, 25.34. MS m/z+548.2 (M+Na), 550.2 (M+2+Na).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[O:12]2)[CH:6]=[CH:7][C:8]=1OC.C[C:25]1[NH:26][C:27]2C(C=1)=CC=CC=2>>[CH3:25][N:26]([CH3:27])[C:8]1[CH:7]=[CH:6][C:5]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[O:12]2)=[CH:4][CH:3]=1.[CH3:22][N:21]([CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1OC
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Product: CN(C)c1ccccc1

Procedure:
Example 1 was repeated except that 32 g of 3-(3', 4'-dimethoxyphenyl)-6-dimethylaminophthalide and 13.5 g of 2-methylindole were used, respectively, instead of 30 g of 3-(p-dimethylaminophenyl)-6-dimethylaminophthalide and 13 g of dimethylaniline to obtain 33 g of triarylmethane having the following structure whose m.p. was 230°-232° C. in the form of colourless crystals (Recrystallized from methanol). This compound becomes bluish violet upon exposure to light on silica gel. ##STR11##
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[C:41]([O:49][C:50](=[O:52])[CH3:51])=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43](O)=[O:44])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[C:41]([O:49][C:50](=[O:52])[CH3:51])=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:44])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.7 %

Procedure:
4-Trifluoromethylaniline (0.159 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.271 mmol, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]([NH2:12])=[CH:8][C:9]=1[CH2:10][CH3:11])[CH3:2].[N+:14]([C:17]1[C:18]([CH:28]=O)=[N:19][N:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:21]=1)([O-:16])=[O:15].S(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]2[NH:12][C:28]([C:18]3[C:17]([N+:14]([O-:16])=[O:15])=[CH:21][N:20]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[N:19]=3)=[N:13][C:6]=2[CH:5]=1)[CH3:2]
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: CCOc1cc(N)c(N)cc1CC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])[nH]c2cc1CC
Temperature: 120 °C
Yield: 52 %

Procedure:
A mixture of 4-ethoxy-5-ethyl-benzene-1,2-diamine [0.18 g, Reference Example 30(s)], 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carbaldehyde [0.225 g, Reference Example 6(m)] and sodium bisulfite (0.12 g, 1.2 mmol) in dimethylformamide (10 mL) was heated at 120° C. for 1 hour. The mixture was cooled, water (100 mL) was added and the aqueous mixture was extracted with twice ethyl acetate (50 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 20-0% heptane) to give 5-ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole (200 mg) as a solid. LC-MS (Method E) RT=2.85 minutes, 386 (M+H)+. (b) 2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1,5,6,7-tetrahydro-1,3-diaza-s-indacene
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Agent: Cl
Product: O=C(CCCN1CCC(NS(=O)(=O)c2ccc(Cl)cc2)CC1)c1ccccc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride may be reacted with p-chlorobenzenesulphonyl chloride to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:23]([Si:26]([CH3:28])([CH3:27])[O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:9][CH:8]=2)[CH2:13]1)([CH3:25])([CH3:24])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc([N+](=O)[O-])nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 1-(6-nitro-pyridin-3-yl)-azetidin-3-ol (154 mg, 0.779 mmol) in 2 mL of DMF is added Et3N (0.2 mL, 0.15 mmol), TBDMSCl (117 mg, 0.776 mmol). The resulting mixture is stirred at room temperature for 2 h. Poured into EtOAc/NaHCO3. the aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layers are ished with brine, dried over Na2SO4. Concentrated to give 5-[3-(tert-butyl-dimethyl-silanyloxy)-azetidin-1-yl]-2-nitro-pyridine (175 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To 44 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid in 100 mL of methanol and 300 mL of chloroform at 0° C. was added 200 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform. The product was then recrystallized from hexanes to give 32.6 g (73%) of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester: melting point 104-105° C. (decomposed); mass spectrum (m/e): M+H 270.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=1[OH:21])=[O:10]>CN(C)C=O.C(OCC)(=O)C>[N+:18]([C:14]1[C:13]2[O:21][CH2:8][C:9](=[O:10])[NH:11][C:12]=2[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2c(cccc2[N+](=O)[O-])N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (4.10 g, 29.7 mmol) was added to a solution of 2-chloro-N-(2-hydroxy-3-nitrophenyl)acetamide obtained (5.70 g, 24.7 mmol) in N,N-dimethylformamide (150 mL) while cooling in ice, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was powdered with chloroform and collected by filtration to afford 8-nitro-2 H-1,4-benzoxazin-3(4 H)-one as a pale orange powder (4.32 g).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([N:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:11])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)NC(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CS(=O)(=O)N(Cc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 1.11 g of methyl 3-[N-(diphenylmethyl) aminosulfonyl]-2(R)-methylpropionate, 447 mg K2CO3, 347 mL benzyl bromide in 20 mL DMF. The reaction was stirred overnight, concentrated in vacuo and partioned between ethyl acetate and water. The organic phase was washed with brine, dried and concentrated in vacuo to 1.2 g of a clear oil. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 730 mg of methyl 3-[N-(benzyl)-N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionate. HRMS (M+Li): calcd. 444.1821, obs 444.1865.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.Cl.CN.C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:31]C1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:32][CH3:31])=[O:10])[CH:7]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (860 mg, 2.37 mmol) and methylamine hydrochloride salt (0.34 g, 4.75 mmol) in 10 mL of DMF was added PyBOP (1300 mg, 2.49 mmol) and TEA (1.13 mL, 8.3 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as an offwhite powder (165 mg, yield 19%). MS calcd for (C16H18BN3O5S): 375.1. MS found (ESI negative): (M−H)−=374.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.87 (s, 1H), 9.17 (bs, 1H), 7.93 (d, J=4.8 Hz, 1H), 7.41 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H)), 6.35 (d, J=8.8, 2 Hz, 1H), 4.87 (s, 2H), 3.77 (s, 2H), 2.63 (d, J=4.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2ccccc2F)cc1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5F)cc4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 4-(2-fluoro-benzyloxy)aniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.72(1H, bs), 9.41(1H, s), 8.91(1H, s), 8.59(1H, d), 8.10(1H, d), 7.65(3H, m), 7.45(1H, m), 7.25(2H, m), 7.18(2H, d), 5.20(2H, s), 2.65(3H, s); m/z (M+1+) 428.