Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH:18]([O:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH:16]([CH:28]=[CH:29][P:30]([O:35]CC)([O:32]CC)=[O:31])[O:15]2)=[C:7]([O:38]C(=O)N(C2C=CC=CC=2)C2C=CC=CC=2)[N:6]=1)(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.Br[Si](C)(C)C>CC#N>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:38])[C:8]2[N:9]=[CH:10][N:11]([CH:14]3[CH:18]([O:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH:16]([CH:28]=[CH:29][P:30]([OH:35])([OH:32])=[O:31])[O:15]3)[C:12]=2[N:13]=1)(=[O:3])[CH3:2]
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(C)=O)nc32)O1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CC(=O)Nc1nc2c(ncn2C2OC(C=CP(=O)(O)O)CC2OC(=O)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
A suspension of compound 9.9 (128 mg, 0.173 mmol) in MeCN (5 mL) was treated with 2,6-lutidine (0.08 mL, 0.7 mmol) and bromotrimethylsilane (0.3 mL, 2.27 mmol) and stirred at room temperature for 2 h. The mixture was evaporated and co-evaporated with MeCN. The residue was dissolved in MeOH—H2O (1:1, 10 mL) and treated with NaOH (1 N, 3 mL). The mixture was stirred at room temperature for 16 h then at 45° C. for 1 h, and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to give the desired product 9.10 (32 mg, 48%). 1H NMR (D2O) δ 2.1 (m, 2H), 4.55 (m, 1H), 4.8 (m, 1H), 5.7 (d, 1H, J=1.5), 5.9 (m, 1H), 6.1(m, 1H), 7.7 (s, 1H). 31P NMR (D2O) d 17.17. LRMS (ESI) MH+ C11H14N5O6P requires 344.2. Found 344.0.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)OCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCN(C(=O)OCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-n-pentyl-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:5]=[C:6](F)[C:7]=1[N+:8]([O-:10])=[O:9].[CH3:20][O-:21].[Na+].Cl.[CH3:24][OH:25]>>[CH3:20][O:21][C:6]1[CH:5]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:3]=[C:2]([O:25][CH3:24])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Reactant: C[O-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1cc(CC(=O)O)cc(OC)c1[N+](=O)[O-]

Procedure:
A stirred solution of t-butyl 3,5-difluoro-4-nitrophenylacetate (4.5 g, Reference Example 14) in methanol (350 mL) was treated with sodium methoxide in methanol (36 g, 25 wt %) and then heated at reflux for 18 hours. The cooled reaction mixture was carefully acidified to pH 2 by addition of dilute hydrochloric acid and then partially evaporated to remove the methanol. The aqueous residue was extracted twice with ethyl acetate. The combined extracts were extracted into saturated sodium bicarbonate solution. The aqueous extract was acidified to pH 2 and extracted with twice with ethyl acetate, then dried and then evaporated to give the title compound (1.4 g) as a brown solid.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH2:3]1.ClCCl.Cl>O1CCOCC1.CO>[NH2:12][C:7]1[C:6]2[C:5]3[C:4](=[N:29][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:27]=2)[CH2:3][CH:2]([OH:1])[C:11]=3[CH2:10][S:9][N:8]=1
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N)=NSC4)c1C
Yield: 48.1 %

Procedure:
A mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (40 mg), dichloromethane (1 mL), a 4 N solution of hydrochloric acid in dioxane (0.5 mL) and methanol (0.5 mL) was stirred at room temperature for two days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (12.5 mg, 48%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[H][H].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: [H][H]
Reactant: CI
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1Cl
Reaction time: 8 h

Procedure:
15.75 g (0.1 mole) of commercially available 2-chloronicotinic acid was dissolved in 100 mL of N,N-dimethylformamide. After cooling this solution to 0° under nitrogen, 4.4 g (0.11 mole) of 60% sodium hydride was added portionwise while evolved hydrogen gas was vented. The reaction mixture was stirred until the effervescence stopped (~2 hrs.). 7.5 mL (0.112 mole) of methyl iodide was then added dropwise. Stirring of the reaction mixture was continued overnight. Solvent was removed in vacuo at r.t. The resulting brown residue was partitioned between ethyl acetate and water. The organic phase was then washed with brine and dried over anhydrous magnesium sulfate. Solvent removal gave a residue which was purified on silica gel using 1:1 ethyl acetate:hexane mixture to give the desired methyl 2-chloronicotinate as oil.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(O)(CC)C.C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][O:28]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)NCC(O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCC(C)(C)O
Product: O=C1COC(c2ccc(OCc3ccccc3)cc2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of KOtBu (6.68 g; 59.5 mmol) in 2-methyl-2-butanol (100 mL) was added dropwise a solution of N-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide (17.30 g; 54.1 mmol) in THF (100 mL). The resulting mixture was stirred for 1 hour at RT and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and treated with a 1M aqueous solution of HCl, at 0° C. The layers were separated and the aqueous layer extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 6-(4-benzyloxy-phenyl)-morpholin-3-one (14.10 g).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>C1COCC1.ClCl>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Agent: ClCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(4,4-diphenylpiperidin-1-yl)butyronitrile (4.65 g, 15.3 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 54 mL, 54 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature and concentrated to a volume of about 40 mL. Aqueous HCl (6N, 55 mL) was added cautiously at 0° C. and stirring was continued for 2 hours at 55°-65° C. The mixture was cooled to 0° C., basified to pH 10 by addition of 6N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2 Cl2 (50 mL) was added HCl in ether (1.0M, 30 mL, 2.0 equiv). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and this solution was added dropwise into ether (150 mL) with swirling. The resulting solid was filtered and washed with ether (100 mL). This solid was taken up in water (30 mL), which was basified to pH 10 by addition of 1M aqueous NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.51 g (95%) of light brown oil, which was characterized spectroscopically.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cu][C:11]#[N:12]>N1C=CC=CC=1>[OH:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: Cc1c(O)cccc1Cl
Solvent: c1ccncc1
Product: Cc1c(O)cccc1C#N

Procedure:
A further process starts from 3-chloro-2-methylphenol (Cresp et al., J. Chem. Soc. Perkin Trans.1, 2435(1974)). This is reacted with copper(I) cyanide in pyridine at boiling heat to give 3-hydroxy-2-methylbenzonitrile. In the second stage, the nitrile is hydrolyzed to 3-hydroxy-2-methylbenzoic acid (2) in 18 hours in a boiling mixture of water, glacial acetic acid and concentrated sulfuric acid. The first stage of this process has the significant disadvantage that very toxic copper(I) cyanide is employed--under the reaction conditions toxic hydrogen cyanide gas can escape from the reaction mixture. Harmful pyridine is employed as a solvent. The reaction is distinguished by difficult working up and a high yield of toxic salts. In the second stage (amide hydrolysis), a very long reaction time is necessary. At the very high reaction temperatures, the acidic reaction medium is very corrosive to the materials customarily employed in chemical plants.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1COS(C)(=O)=O
Yield: 99 %

Procedure:
The product of Example 54B (4.2 g, 12 mmol) was treated with methanesulfonyl chloride according to the procedure described in Example 38G. The title compound was obtained as a brown oil (5.10, 99% yield). 1H NMR (MeOH-D4, 300 MHz) δ 1.46 (s, 9H), 2.80 (m, 1H), 3.08 (s, 3H), 3.40 (m, 2H), 3.70 (m, 2H), 4.16 (m, 1H), 4.35 (m, 2H), 5.16 (s, 2H), 7.30 (m, 5H); MS (DCI/NH3) m/z 446 (M+NH4)+, 429 (M+H)+.
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N)c1ccccc1
Reaction time: 6 h

Procedure:
3.7 g (10 mmol) of methyl 3-azido-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate (Ex. 2) are dissolved in 20 ml of methanol/ethyl acetate (1:1), treated with 400 mg of Pd/C 10% and stirred for 6 h under a hydrogen atmosphere. After filtering off the catalyst and concentrating, a colorless oil is obtained which solidifies after a few days.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C:21](=[O:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.[CH3:26]C(C)([O-])C.[K+].O>CI.C(O)(C)(C)C>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C:21](=[O:23])[C@@:20]4([CH3:26])[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C3OCCOC3C[C@@H]12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]3CC4OCCOC4[C@@]3(C)CC(=O)[C@]21C
Reaction time: 18 h

Procedure:
To a stirred, ice cooled solution of 10.5 g of 17-ethylenedioxy-3-methoxyestra-1,3,5(10)-trien-11-one in 300 ml of methyl iodide under an atmosphere of nitrogen is added, over 10 minutes, 120 ml of a 1.1 molar solution of potassium tert.-butoxide in t-butyl alcohol. The temperature is allowed to rise to room temperature and the mixture is then stirred for 18 hours. It is next poured onto 500 ml of water and extracted with methylene chloride, twice. The combined organic extracts are washed with water and dried over sodium sulfate. Removal of the solvent gives an oil which is crystallized from ether to yield 17-ethylenedioxy-3-methoxy-9α-methylestra-1,3,5(10)-trien-11-one, m.p. 142° - 145° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5([C:37]#[N:38])[CH2:36][CH2:35]5)[CH:29]=4)[CH:25]=3)[CH:16]=[CH:15][C:13]=2[N:14]=1.O1C=C(C(O)=O)N=C1.C(Cl)(=O)C(Cl)=O>CN(C)C(=O)C.CN(C)C=O.O1CCCC1>[C:37]([C:34]1([C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([NH:26][C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=2[CH3:40])[O:19][C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([NH:9][C:6]([C:4]4[N:3]=[CH:2][O:1][CH:5]=4)=[O:7])[S:11][C:12]=3[CH:18]=2)=[O:39])[CH2:36][CH2:35]1)#[N:38]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=C(Cl)c1cocn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cocn1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 1,3-oxazole-4-carbonyl chloride synthesized above in N,N-dimethylacetamide (3 mL) was added N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) produced in Example A3(iv), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of 1,3-oxazole-4-carbonyl chloride synthesized in the same manner as in the above from 1,3-oxazole-4-carboxylic acid (30 mg, 0.265 mmol), oxalyl chloride (27 μL, 0.316 mmol), N,N-dimethylformamide (1 drop) and tetrahydrofuran (1 mL) in N,N-dimethylacetamide (1 mL), and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, diluted with 5% aqueous sodium hydrogencarbonate solution (200 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate/hexane to give the title compound (3.84 g, 75%) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C(N(CC)CC)C>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][C:15]([O:14][CH3:13])=[O:18])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNc1ccc(F)cc1[N+](=O)[O-]
Yield: 74.7 %

Procedure:
A mixture of 2,5-difluoronitrobenzene (54.6 g, 343 mmol), glycine methyl ester hydrochloride (47.3 g, 374 mmol) and triethylamine (114.5 mL, 818 mmol) was heated at 65° C. (internal temperature) in THF (1500 mL) over a 3 night period. Additional glycine methyl ester hydrochloride (30 g) and triethylamine (20 mL) were added and the heating continued for a further 2 nights. The mixture was cooled, filtered and evaporated to dryness. The residue was treated with 5M hydrochloric acid and the orange solid was filtered off, washed well with water (total ˜2 L) and dried under vacuum to give the product (58.5 g). The product was then extracted with ethyl acetate (600 ml total), filtered and evaporated. The residue was slurried with water (1 L), filtered and dried to give product (40 g, 51%).
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][OH:26]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([NH:23][CH2:24][CH2:25][OH:26])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Product: O=C(Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)NCCO

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and 2-aminoethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH2:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].NC1C=CC=CC=1.C(CC(OCC)=O)(=O)CC.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[N:55]([C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)[N:54]=[N:53][N:52]=2)=[CH:41][CH:40]=1>CN1C(=O)CCC1.O>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[C:51]3[N:55]([C:56]4[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=4)[N:54]=[N:53][N:52]=3)=[CH:43][CH:44]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CCC1=Nc2ccccc2C(=O)C1
Agent: CCOC(=O)CC(=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Nc1ccccc1
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
A mixture of 2-ethyl-4-quinolone (1.9 g; 11 mmol), (prepared using a similar procedure to that described in Org. Syn., Coll., Vol. III, p. 374 and p. 593 from aniline and ethyl propionylacetate), and potassium carbonate (2.28 g; 16 mmol) in NMP (75 ml) was heated at 60° C. for 20 minutes with stirring. Compound E (5.2 g; 10 mmol) was added and the reaction mixture heated at 80° C. for 90 minutes. The mixture was allowed to cool to ambient temperature and water (150 ml) was added. The resultant precipitate was collected by filtration, dried at 60° C., then recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (1.5 g) as a solid, m.p. 204°-206° C.; NMR (CDCl3): 1.42(3H, t), 3.0(2H, q), 5.23 (2H, s), 6.67(2H, d), 6.75(1H, s), 6.85(2H, d), 7.25(2H, d), 7.43(1H, d), 7.55(1H, t), 7.70(3H, m) 7.90(3H, d), 8.05(1H, d), 8.20(1H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12][OH:13]>[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:12][OH:13])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cccc(C=NO)c1
Yield: 78.7 %

Procedure:
3-Nitrobenzaldehyde (6 g, 40 mmol) was added to a solution of hydroxylamine (15 g, 216 mmol) in 5% aqueous sodium hydroxide solution (120 ml). Filtration and drying afforded the title compound as a white solid (5.23 g, 79%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[CH2:5])C.O.[Br:25]N1C(=O)CCC1=O>O1CCCC1.ClCCl>[Br:25][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[O:5]
Reactant: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
To a solution of 123 mg of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 4 mL of tetrahydrofuran are added 1 mL of water and then, after cooling to 0° C., 71 mg of N-bromosuccinimide. The reaction mixture is stirred for 2.5 hours at room temperature and then diluted with 80 mL of dichloromethane. The organic phase is washed with water and then dried and concentrated to dryness under reduced pressure to give 60 mg of crude 6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid (containing small amounts of 6-acetyl derivative and dibromo derivative) that is used without further purification.
Reaction SMILES: [N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.P(Br)(Br)Br>>[N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25]([NH2:1])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Agent: BrP(Br)Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N#N
Solvent: ClP(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(N)=O

Procedure:
An N2 -naphthalenesulfonyl-L-argininamide is prepared by reaction of a corresponding N2 -naphthalenesulfonyl-L-arginyl halide and an amine. The N2 -naphthalenesulfonyl-L-arginyl halide is prepared by reacting a corresponding N2 -naphthalenesulfonyl-L-arginine with a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, etc.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]([NH:9][CH:10]1[C:20]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=2[C:18]2[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:28][CH3:29])[C:17]=2[O:26][CH3:27])[CH2:12][CH2:11]1)=[O:8].O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[S:2]([OH:5])([O:25][C:22]1[CH:23]=[CH:24][C:19]2[C:18]3[C:17]([O:26][CH3:27])=[C:16]([O:28][CH3:29])[C:15]([O:30][CH3:31])=[CH:14][C:13]=3[CH2:12][CH2:11][C@H:10]([NH:9][C:7](=[O:8])[CH3:6])[C:20]=2[CH:21]=1)(=[O:4])=[O:3]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OS(=O)(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Chlorosulphonic acid (1 ml) was added at 0° C. in portions to a solution of pyridine (10 ml). After 15 minutes at 0° C., a solution of N-acetyl-colchicinol (1 g, 2.8 mmol) in pyridine (10 ml) was added. The solution was stirred overnight at ambient temperature. Water (30 ml) was added and the mixture was adjusted to pH8 by addition of sodium hydrogen carbonate. The aqueous layer was extracted with ether (3×20 ml) and purified on HP20SS resin, eluted with a 0–40% gradient of methanol/water. The volatiles were removed by evaporation to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl hydrogen sulphate as a white solid.