Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][NH2:27].CC([O-])=O.[Na+]>CCO>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][N:27]=[C:16]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:17][CH3:18]
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 65.3 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (3.21 mg, 10.17 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (3.16 mg, 10.68 mmol) and anhydrous NaOAc (876 mg, 10.68 mmol) in EtOH (120 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 2:3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2PE to give N-{2-[1-(2,4-bistrifluoromethylbenzyloxyimino)propyl]-4-chlorophenyl}trifluoromethanesulfonamide 76 (3.70 g, 65%), as a pale yellow oil. 1H n.m.r. (200 MHz, CDCl3) δ 10.96, br s, 1H; 7.96, s, 1H, 7.85+d, J=8.4 Hz, 1H, 7.72, d, J=8.4 Hz, 1H, 7.61, d, J=8.8 Hz, 1H, 7.49, d, J=2.4 Hz, 1H, 7.33, dd, J=2.4 and 8.8 Hz, 1H, 5.45, s, 2H, 2.88, q, J=7.6 Hz, 2H, 1.21, t, J=7.6 Hz, 3H. HRMS (M+) 556.0254.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].Cl[CH2:12][CH:13]=[CH:14][CH3:15].ClC(C)C=C>CO>[CH2:12]([S:10][C:9]1[CH:8]=[CH:7][O:6][C:5]=1[CH3:4])[CH:13]=[CH:14][CH3:15]
Reactant: Cc1occc1S
Reactant: CC=CCCl
Agent: C=CC(C)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC=CCSc1ccoc1C
Temperature: 33 °C
Reaction time: 0.17 h

Procedure:
Into a 50 ml round bottom 1 neck flask equipped with nitrogen inlet tube, "Y" tube, reflux condenser, magnetic stirrer, and cold water bath is placed a solution containing 0.54 g of sodium methylate (0.01 moles) in 6 ml of anhydrous methanol. 1.14 g (0.01 moles) of 2-methyl-3-furan thiol in 6 ml of anhydrous methanol is then added to the sodium methylate solution. The reaction mass is stirred for a period of 10 minutes, with cooling, maintaining the temperature thereof between 24° and 30° C. 0.91 g (0.01 moles) of a mixture of 80% 1-chloro-2-butene and 20% 3-chloro-1-butene dissolved in 2 ml of anhydrous methanol is then added over a 4 minute period warming to 33° C. The reaction mass is allowed to cool to 23° C. and remains at that temperature, with stirring, for a period of 2.5 hours, at which time it is concentrated to 7 ml on a rotary evaporator using water aspirator vacuum. 20 ml water is then added and the reaction mass is neutralized to a pH of 5 - 6 using 4% hydrochloric acid. The reaction mass is extracted with three 10 ml portions of n-hexane. The hexane extracts are combined, washed with 2 ml saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated using a rotary evaporator to yield 1.24 g of a yellow oil.
Reaction SMILES: [C:1]([C:4](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])(=O)[CH3:2].[NH2:26][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:28][C:29]([O:31][CH2:32]C)=[O:30]>>[CH3:2][C:1]1[NH:26][C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6]
Reactant: CCOC(=O)C=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Product: COC(=O)C1=C(c2ccccc2)NC(C)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
More specifically a mixture of 330 mg (1 mmol) of t-butyl 2-[N-[2-acetyl-3-(3-nitrophenyl)-2-propenoyl]-amino]acetate and 191 mg (1 mmol) of ethyl 3-amino-3-phenyl-2-propenoate was stirred under a light-shielding condition at 110° C. overnight. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 98 mg (22%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[NH:13][C:12]=3[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]([CH3:26])[C:12]=3[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)n(C)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1H-benzimidazole-6-carboxylate (125 mg, 0.365 mmol) and cesium carbonate (297 mg, 0.913 mmol) in N,N-dimethylformamide (0.730 mL) was added methyl iodide (0.025 mL, 0.402 mmol). Stirred at ambient temperature for 2.5 h. Filtered and purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (40 mg): LC-MS [M+1]=357.2.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)cc(C(F)(F)F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluoro-5-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=O)[N:16]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].S(O)(O)(=O)=O.[C:27]([NH:30][C:31]([NH2:33])=[O:32])(=[NH:29])[NH2:28]>CO>[NH:30]([C:27]1[N:29]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[N:16]=[C:15]([C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[OH:12])[N:28]=1)[C:31]([NH2:33])=[O:32]
Reactant: O=c1nc(-c2ccc([N+](=O)[O-])cc2)oc2ccccc12
Reactant: N=C(N)NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: NC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)nc(-c2ccccc2O)n1

Procedure:
A solution of 8.9 g (385 millimoles) of sodium in 400 ml of methanol is added dropwise, while stirring, to a suspension of 93.9 g (350 millimoles) of 2-(4-nitrophenyl)-4H-1,3-benzoxazin-4-one and 58.1 g (192.5 millimoles) of guanyl urea sulfate in 1 liter of methanol. Subsequently, the mixture is refluxed for 30 minutes. After cooling of the mixture, the precipitate formed is suction-filtered, washed with water and methanol and dried at 70°C in a vacuum drying oven. The yield is 61.9 g (50.2 % of the theoretical yield). The 4-ureido-2-(2-hydroxyphenyl)-6-(4-nitrophenyl)-s-triazine obtained is a powder having a light yellow color and a melting point of 249°C (decomposition).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[C:25](OC([O-])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(Cl)(Cl)Cl>[C:28]([O:27][C:25]([NH:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)OC(C)(C)C)CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (20 g) was dissolved in chloroform (200 ml). tert-Butyl dicarbonate (13.4 g) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The mixture was washed with a saturated aqueous sodium hydrogen-carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 23.85 g of 9-(tert-butoxycarbonylaminomethyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:10]1([C:9]2([CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])[CH2:21][CH2:22]3)[CH2:2][O:16]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(C2(c3ccccc3)CO2)CC1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
A mixture of trimethylsulfoxonium iodide (2.402 g, 10.91 mmol) and sodium hydride (0.436 g, 10.91 mmol) in THF (20 mL) was heated at 55° C. for 3 h then a solution of compound 87 (2.82 g, 8.73 mmol) in THF (10 mL) was added. The reaction mixture was stirred for 36 h, quenched with water, extracted with ether and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated to afford compound 88 used as a crude in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[O:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1ccc(C(=O)O)o1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)o1
Yield: 53 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.0 mg (0.084 mMol) 5-methylfuran-2-carboxylic acid, 6.8 mg (53%) of the title compound were recovered as a beige solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:19][O:1][CH2:2][C:3]2[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cccc(COCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(6-Hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (1.04 g, Papadopoulou,; J. Heterocycl. Chem., 32, 1995, 675) in DMF (25 mL) was treated with sodium hydride (0.64 g, 60% suspension in oil), the mixture was then stirred for 1 h at RT, bromomethyl cyclopropane (0.688 g) was added dropwise and stirring was continued for further 1.75 h. The reaction mixture was partitioned between 2 M aqueous KHCO3 and AcOEt, the layers were separated, the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with saturated aqueous NaCl and water, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 50%) to N-(6-cyclopropylmethoxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.884 g) as a yellow oil. MS (ESI): 263.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[N:6][CH:7]=1.[N+](C1C=CC(S(O[CH2:38][C@H:39]2[CH2:41][C:40]2([F:43])[F:42])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:42][C:40]1([F:43])[CH2:41][C@@H:39]1[CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[N:13]=[CH:12][C:11]=3[N:24]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)cn3)nc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OC[C@H]4CC4(F)F)cn3)nc2cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A suspension of N-((2S)-1-((2-(5-hydroxypyridin-2-yl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide (37.4 mg), ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate (50.1 mg) and potassium carbonate (31.5 mg) in DMF (5 mL) was stirred at 70° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained solid was washed with diethyl ether to give the title m compound (12.4 mg).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([C:8](=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=2[F:24])[CH:10]=1)[CH3:7])C.[F:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:7][N:6]([CH2:5][C:4]([OH:3])=[O:26])[C:8](=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=3[F:27])=[CH:19][C:18]=2[F:24])[CH:10]=1
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(Br)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)O)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2F)c1
Temperature: 150 °C

Procedure:
A mixture of {{[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester (600 mg, 1.51 mmol), 2,4,5-trifluorophenylboronic acid (400 mg, 2.27 mmol), Pd(dppf)Cl2 methylene chloride complex (37 mg, 0.045 mmol), potassium carbonate (520 mg, 3.8 mmol), DMF (12 mL) and water (3 mL) was degassed, flashed with nitrogen, heated at 150° C. for 60 minutes in microwave reactor. The mixture was acidified by conc. HCl and diluted with water. Solvent was then removed by decantation and the sticky residue was purified by preparative HPLC to afford {{methyl-[3-(3,2′,4′,5′-tetrafluoro-biphenyl-4-yloxymethyl)-benzoyl]-amino}-acetic acid, 171 mg (25%). LC-MS (ES) calculated for C23H17F4NO4, 447; found m/z 448 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:18][Br:19].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:37]1[CH2:42][O:41][CH:40]=[CH:39][CH2:38]1.O>C(Cl)Cl>[Br:1][C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:40]3[CH2:39][CH2:38][CH2:37][CH2:42][O:41]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:18][Br:19]
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c(CBr)c(Br)sc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(CBr)c(Br)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 g, 6.1 mmol) and PPTS (153 mg, 0.61 mmol) in DCM (25 mL) at 0° C. was added DHP (2.00 g, 24.5 mmol) dropwise. The reaction was stirred at RT for 18 h, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:1) to give 6-bromo-5-(bromomethyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 56.7% yield) as a yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[CH:16][CH:15]=3.C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:16]([N+:1]([O-:4])=[O:2])[CH:15]=3
Reactant: CC1(C)C(=O)Oc2ccc3ccc(Cn4cncn4)cc3c21
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)Oc2ccc3cc([N+](=O)[O-])c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Nitric acid (72% by weight, 0.045 ml) was added dropwise to a stirred, ice-cooled mixture of 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone (0.44 g) and acetic anhydride (6 ml). The mixture was stirred at room temperature for 18 h, then added to a stirred mixture of aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography. Elution with ethyl acetate:pentane, 3:1 v/v, gave 1,1-dimethyl-7-nitro-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 183°-185° after recrystallisation from ethyl acetate. (Example 13).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:21]([CH3:32])[O:20][C@H:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:21]([CH3:32])[O:20][C@H:12]([S:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:51])[C@H:11]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CO[C@H]2[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2S(=O)c2ccccc2)cc1
Temperature: -20 °C

Procedure:
To a solution of phenyl 6-deoxy-3,4-di-O-benzoyl-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-13, prepared above) (400 mg, 0.7 mmol) in 10 mL of CH2Cl2 at -78° C. is added a solution of mCPBA (170 mg, 1.1 mmol) in 2 mL of CH2Cl2. The reaction mixture is allowed to warm to -20° C. and then quenched with TEA (500 μL, 3.59 mmol). The reaction mixture is diluted with 10 mL of CH2Cl2, washed with saturated NaHSO3 (10 mL), saturated NaHCO3 (10 nL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (EtOAc/petroleum ether) to give 1,6-dideoxy-3,4-di-O-benzoyl-2-O-(4-methoxybenzyl)-1-(phenylsulfinyl)-β-L-allopyranose as a mixture of diastereomers.
Reaction SMILES: C(OC([CH:11]1[NH:23][CH2:22][C:20]2=[C:21]3[C:16](=[C:17]([C@H:24]4[C@H:28]([C:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[NH:31][CH:30]=5)[C:27](=[O:38])[NH:26][C:25]4=[O:39])[CH:18]=[CH:19]2)[CH:15]=[CH:14][N:13]3[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C@H:28]2[C@H:24]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:22][NH:23][CH2:11][CH2:12][N:13]5[C:21]=4[C:16]=3[CH:15]=[CH:14]5)[C:25](=[O:39])[NH:26][C:27]2=[O:38])=[CH:30]1
Reactant: O=C(OCc1ccccc1)C1Cn2ccc3c([C@@H]4C(=O)NC(=O)[C@H]4c4c[nH]c5ccccc45)ccc(c32)CN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2ccc3c4c2ccn4CCNC3)[C@@H]1c1c[nH]c2ccccc12

Procedure:
(±)-Trans-7-[4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-3-yl]-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carb oxylic acid benzyl ester (161 mg, 0.31 mmol) and 10% palladium on carbon (100 mg) in anhydrous methanol (15 ml) were stirred under 1 atmosphere of hydrogen for 16 hours. The catalyst was then filtered through a bed of Celite and the filtrate evaporated to dryness to yield (±)-trans-3-(1H-indol-3-yl)-4-(1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-pyrrolidine-2,5-dione as an off white solid (95 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.04 (d, 1H, J=1.6 Hz), 7.35-7.42 (m, 4H), 7.24 (dd, 1H, J=2.8 and 5.6 Hz), 7.09 (t, 1H, J=7.2 Hz), 6.89-6.98 (m, 3H), 4.52 (dd, 2H, J=7.2 and 24.8 Hz), 4.11 (s, 2H), 4.07-4.10 (m, 2H), 3.14-3.17 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[N:18]=2)=[O:15])[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38](Cl)=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:1][C:2]3[CH:3]=[C:4]([CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][NH:19][N:18]=3)=[O:15])=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 160 °C
Yield: 11.6 %

Procedure:
A solution of 1,1-dimethylethyl 3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate (157 mg, 0.4 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (95 mg, 0.48 mmol) in acetonitrile (2 mL), containing potassium carbonate (111 mg, 0.8 mmol), was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane to give a product which was further purified by chromatography on silica, eluting with 0-8% methanol in ethyl acetate, to give the required product as a white foam (21 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Br:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[C:14]2=[O:19]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3c(Br)cccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 2.5 mL, 5.0 mmol) was added to a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (4-bromo-1-indanone, 960 mg, 4.55 mmol) in THF (9.1 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (1.25 g, 5.46 mmol) in THF (5 mL) was added via cannula. The reaction mixture was allowed to warm to room temperature naturally. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (330 g column, hexanes→30% EtOAc/hexanes, gradient) to afford 72 mg (4%) of methyl 4-((4-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)benzoate.