Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(OCC)(=O)C>ClCCl.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][O:15][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1=COCCC1
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×100 ml), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil (750 mg, 2.4 mmol, 80%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>CC(O)C.[Cu](I)I>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(I)cc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
A mixture of 4-iodoaniline (0.654 g, 3 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 3.6 mmol), potassium phosphate (1.272 g, 6 mmol), ethylene glycol (0.33 ml) and copper iodide (0.03 g, 0.15 mmol) in 2-propanol (3 ml) was placed under argon in a sealed-tube and heated to 80° C. for 30 hours. After being cooled to room temperature, the medium was washed with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 43a (0.36 g, 1.3 mmol, 43%) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3](=O)[CH2:4][C:5]#[N:6].[OH-:17].[Na+].S(O)(O)(=O)=O.[NH2:24]O>O>[CH3:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[O:17][N:24]=1)([CH3:16])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: CC(C)(COC1CCCCO1)C(=O)CC#N
Reactant: NO
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(COC1CCCCO1)c1cc(N)on1
Temperature: 25 °C
Yield: 117.9 %

Procedure:
To a stirred solution of 134 g (0.60 mol) of 4,4-dimethyl-3-oxo-5-(tetrahydro-pyran-2-yloxy)-pentanenitrile and 51.3 g (1.28 mol) of sodium hydroxide in water (1.3 L) are added 48.9 g (0.30 mol) of hydroxylamine sulfate. The reaction mixture is stirred at reflux for 18 h. After this time, the reaction mixture is cooled to room temperature and extracted with ethyl acetate (3×0.8 L). The organic layers are combined and washed with brine (1 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residual brown oil is triturated with hexanes (0.8 L) while stifling and the resulting precipitate is isolated by filtration and dried in a vacuum oven for 2 d to yield 85 g of 3-[1,1-dimethyl-2-(tetrahydropyran-2-yloxy)-ethyl]-isoxazol-5-ylamine as a yellow solid. Yield 60%; m/z 241 [M+H], 157 [M+H—C5H8O]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (3H, s), 1.19 (3H, s), 1.45-1.75 (6H, m), 3.26 (1H, d, J=9.3 Hz), 3.4 (1H, m), 3.59 (1H, d, J=9.3 Hz), 3.68 (1H, m), 4.5 (1H, m), 4.88 (1H, s), 6.43 (2H, s).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH2:9]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.[Cl:25][C:26]1[C:31]2[NH:32][C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[NH:35][C:36](=O)[C:30]=2[CH:29]=[CH:28][CH:27]=1.N>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:25][C:26]1[C:31]2[NH:32][C:33]3[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=3[N:35]=[C:36]([N:22]3[CH2:23][CH2:24][N:19]([CH2:9][C:10]4[CH:18]=[CH:17][C:16]5[O:15][CH2:14][O:13][C:12]=5[CH:11]=4)[CH2:20][CH2:21]3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C1Nc2ccccc2Nc2c(Cl)cccc21
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Clc1cccc2c1Nc1ccccc1N=C2N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
To a stirred solution of anisole (0.40 mL, 3.68 mmol) in dry toluene (2.00 mL) was added titanium tetrachloride (0.24 mL, 2.18 mmol) at room temperature under argon. The mixture was then treated with 1-piperonylpiperazine (2.07 g, 9.40 mmol) and 4-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (0.49 g, 2.00 mmol) (Giani et al, supra) and diluted with toluene (1.00 mL). After more 1-piperonylpiperazine (1.19 g, 5.40 mmol) was added, toluene (8.00 mL) was added and the resulted reaction mixture was heated at reflux for 6 h before it was cooled to 60° C. Isopropanol (0.80 mL), celite (0.40 g) and ammonia (30%, 0.50 mL) were added sequentially and the whole mixture was filtered hot. Upon cooling to room temperature, the filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexanes (1/2) as the eluent. Thus 0.63 g (70%) of the title compound was afforded as a light yellow solid; m.p. 160°-162° C; MS 447 (M+ +1).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CN
Reactant: Clc1nccnc1Nc1ccccc1
Product: CNc1nccnc1Nc1ccccc1
Yield: 57.3 %

Procedure:
3-chloro-N-phenylpyrazin-2-amine (4.5 g, 21.22 mmol) was stirred with methyl amine (20.59 g, 20.9 mmol, 33 wt % in THF) under reflux overnight. The solvent was evaporated and the residue was purified by column chromatography using 50% ethyl acetate and hexanes to give N2-methyl-N3-phenylpyrazine-2,3-diamine (2.4 g, 54.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([O:25]C)[CH:18]=4)[N:13]=[C:12]([OH:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1>Br>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:25])[CH:18]=4)[N:13]=[C:12]([OH:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1OC
Agent: Br
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)c(O)c3)c(=O)c12
Yield: 67.8 %

Procedure:
7-Chloro-4-hydroxy-2-(3,4-dimethoxyphenyl)-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (1.00 g, 2.50 mM) was refluxed in 48% HBr (40 mL)for 6 hours to give an orange suspension. Heat was removed and the suspension was filtered while still warm. The collected solids were washedwith water and then ether to give the crude product (0.94 g) as a yellow powder. This material was recrystallized from refluxing methanol (600 mL) to give the title compound (0.63 g, 68%) as a yellow powder, mp=269°-272° C.; MS(CI): 372 (M+H).
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[C:28]([O:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)(=[O:30])[CH3:29]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC1(CCN2C(=O)CSC2CCCc2ccc(C(=O)O)cc2)CCCCC1
Temperature: 0 °C

Procedure:
A solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoldinyl]propyl}benzoic acid (3.9 g., 0.01 mole) and acetic anhydride (1.2 g., 0.012 mole) in pyridine (15 ml.) is kept at 25° C. for 5 days. It is then poured into 50 ml. of ice water and the mixture brought to pH 5.0 by the addition of 2 N hydrochloric acid. The oily product is extracted into chloroform and purified by column chromatography on silica gel with elution by 2% methanol in chloroform.
Reaction SMILES: I[C@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[O:15]1[C@@H:2]2[C@H:13]1[CH2:14][C@H:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:4][CH2:3]2
Reactant: CCO
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@@H]1CC[C@@H]2O[C@@H]2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem., 1996, Vol. 61, p. 8687) (14.3 g) was dissolved in ethanol (130 ml), a 2N aqueous solution (34.5 ml) of sodium hydroxide was added under ice cooling, and the mixture was then stirred at room temperature for 7 hours. After the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with dichloromethane, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=83:17) to obtain the title compound (6.54 g) as a colorless oil.
Reaction SMILES: C([NH:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)C.[OH-].[Na+]>Cl.C(O)C.O.C(Cl)Cl>[NH2:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1
Reactant: CC(=O)Nc1ccccc1Cc1nc(-c2ccncc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: Nc1ccccc1Cc1nc(-c2ccncc2)cs1
Yield: 69.5 %

Procedure:
A solution of 2-(o-acetamidobenzyl)-4-(4-pyridyl)thiazole (2.30 g, 0.007 mol) in concentrated hydrochloric acid (2 mL) and ethanol (3 mL) was refluxed for 3 hours, allowed to cool, diluted with water (2 mL) and methylene chloride (5 mL), and basified with 2.5N sodium hydroxide. The layers were separated and the aqueous layer reextracted with chloroform (2×). The combined organic extracts were dried over potassium carbonate, concentrated, and chromatographed through a short column of silica gel to afford 2-(o-aminobenzyl)-4-(4-pyridyl)thiazole (1.30 g, 65%). mp. 179°-181° C. dec.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:28])[CH:20]=[C:21]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:29][NH2:30]>>[F:28][C:19]1[CH:20]=[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:15]2[O:14][CH:13]([CH2:12][NH:30][CH3:29])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cccnc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cccnc3)c2O1

Procedure:
The title compound was prepared (0.056 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.50 mmol) and methylamine (0.155 g, 5.0 mmol). mp 255-257° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26]I)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[CH3:31][SH:32]>CN(C)C=O.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][S:32][CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS
Reactant: O=C(O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-iodomethyl-4-benzoyloxypyrrolidine (1.05 g) was dissolved in 10 ml of dimethylformamide, and a solution of 1.40 g of 15% methylmercaptan sodium salt in water was added thereto, followed by stirring at room temparature for 30 minutes under a nitrogen stream. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-methylthiomethyl-4-benzoyloxypyrrolidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=2)[CH2:9]1)=O)(C)(C)C>CO.Cl.O1CCOCC1>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Brc1cncc(O[C@@H]2CCCNC2)c1
Yield: 120.1 %

Procedure:
A solution of (R)-3-(5-bromo-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (596 mg, 1.7 mmol) in MeOH (5 mL) and HCl solution in 1,4-dioxane (4N; 1.5 mL) is stirred at room temperature for 16 h. The mixture is concentrated to provide 525 mg 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4][C:3]1=[N:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)C.C([BH3-])#N.[Na+].Cl[O-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)NN=C1CCCC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCCC1(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 51.7 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylcyclopentylidene)hydrazinecarboxylate (4.6 g) and acetic acid (9.4 g) in THF (80 mL) was added sodium cyanoborohydride (5.1 g) at room temperature. The reaction mixture was stirred at 85° C. for 10 hr, aqueous sodium hypochlorite solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (2.4 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:9][CH2:10][C:11]([NH2:13])=[O:12]>C(#N)C>[Br-:9].[NH2:13][C:11]([CH2:10][N+:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)=[O:12]
Reactant: C1CN2CCN1CC2
Reactant: NC(=O)CBr
Solvent: CC#N
Product: NC(=O)C[N+]12CCN(CC1)CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.8 %

Procedure:
To a stirred solution of 1,4-diazabicyclo[2.2.2]octane (17.93 g, 0.1599 mol) in 200 ml of acetonitrile at 0° C. was added dropwise a solution of 2-bromoacetamide (20.05 g, 0.1453 mol) in 200 ml of acetonitrile during 25 min. A precipitate began depositing several minutes into the addition. The milky-white reaction mixture was stirred and allowed to warm to room temperature overnight. After 20 h, the white solid was isolated by filtration, washing with ~200 ml of acetonitrile. Drying in vacuo gave 33.37 g of white solid. This material was combined with product from a previous preparation giving a total of 37.93 g for recrystallization. The solid was dissolved in ~230 ml of boiling ethanol, filtered while hot, and allowed to cool slowly overnight. The solution was seeded while still very warm. The mother liquors were decanted from the dense crystalline mass and the crystals were washed three times with cold ethanol (~50 ml total). Drying in vacuo gave 30.47 g of 1 as large colorless hygroscopic prisms, mp 194°-198° C.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2)c(OC)c1
Reaction time: 2 h

Procedure:
While cooling with ice, 5.00 g of phenylmethanesulfonyl chloride were initially charged in 40 ml of dichloromethane, and a solution of 8.04 ml of 2,4-dimethoxybenzylamine in 10 ml of dichloromethane was slowly added dropwise. For improved stirrability, a further 25 ml of dichloromethane were added, and the reaction mixture was allowed to come to room temperature. After stirring for 2 hours, the reaction mixture was washed with 100 ml of water, with 100 ml of 0.2 N aqueous hydrochloric acid, with 100 ml of saturated aqueous sodium hydrogencarbonate solution and finally once more with 100 ml of water. The organic phase was dried over Na2SO4, concentrated by rotary evaporation and dried under high vacuum. The residue (8.42 g) was used in the next reaction without further purification.
Reaction SMILES: O[C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH3:17])[C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:20])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:20][C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH3:17])[C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2cnn(C)c2[nH]c1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(Cl)c2cnn(C)c2[nH]c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of ethyl 4-hydroxy-1-methyl-6-oxo-6,7-dihyrdo-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate (10 g, 42.2 mmol) in acetonitrile is treated with benzyl triethyl ammonium chloride (40.4 g, 169 mmol), followed by phosphorous oxychloride (17.6 mL, 190 mmol), heated at 40° C. for 0.5 h, then at reflux temperature for 2.5 h, cooled to room temperature, diluted with water (caution exotherm), stirred at ambient temperatures for 16 h and filtered. The filtercake is washed with cyclohexane and dried in vacuo to give the title compound as a white solid, 7.87 g (73% yield), identified by HNMR analysis.
Reaction SMILES: B.[CH2:2]=[C:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.[OH-:17].[Na+].OO>C1COCC1.CCCCCC>[OH:17][CH2:2][CH:3]1[CH2:9][O:8][CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1
Reactant: C=C1COCCN(C(=O)OC(C)(C)C)C1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCOCC(CO)C1
Temperature: 25 °C

Procedure:
1M borane in THF (450 mL, 0.45 mol, 0.9 eq) was added under stirring and cooling on an ice bath to a stirred in a stream of argon solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate (Preparation 79, 107 g, 0.5 mol, 1 eq) in THF (300 mL). The reaction mixture was heated to 25° C. and stirred at this temperature for 3 h. Then the reaction mixture was cooled to 0-10° C. and treated at this temperature sequentially with 3N sodium hydroxide (170 mL) and 30% hydrogen peroxide (66 mL). The obtained homogenous mixture was stirred overnight, then treated with hexane (45 mL), and dried over potassium carbonate. The organic layer was decanted from the precipitate, which was washed with DCM. The organic layers were evaporated in vacuo, and the residue was purified rapidly (due to instability of the product on silica gel) by chromatography (carbon tetrachloride/chloroform/isopropanol 100:0:0→0:100:0→0:90:10) on silica gel (1.2 kg; 63-100 μm) to give title compound as a colorless oil in (85 g, 0.368 mol, 72%).
Reaction SMILES: C(OC([CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][C@H:18]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35]([OH:37])=O)=[CH:34][C:28]=3[N:27]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[OH-:38].[NH4+:39]>>[C:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([C@@H:18]([NH:17][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:8][NH:17][C:15](=[O:16])[O:38][C:9]([CH3:14])([CH3:10])[CH3:8])[CH2:10][CH2:11]3)=[O:16])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][C:28]=2[CH:34]=1)(=[O:37])[NH2:39]
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(C(=O)O)ccc3[nH]2)CC1
Reactant: [NH4+]
Reactant: [OH-]
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(C(N)=O)ccc3[nH]2)CC1

Procedure:
The compound from Example 43 Part A (23 mg, 0.044 mmol) was subjected to the conditions described for Example 1 Part C with the exception that ammonium hydroxide was used in place of 4-amidinobenzoic acid hydrochloride to provide 18 mg of the desired product (79%). MS 520.0 (M+H)+.
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][NH2:6].F[C:9]1[C:22]2C(=O)[C:20]3[CH:19]=[N+:18]([O-:24])[CH:17]=C[C:15]=3[C:14](=[O:25])[C:13]=2[C:12]([O:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:11][CH:10]=1>C1COCC1.O>[C:33]1([CH3:36])[CH:32]=[CH:31][C:30]([S:27]([O:26][C:12]2[CH:11]=[CH:10][C:9]3[NH:6][N:5]=[C:4]4[C:3]5[CH:17]=[N+:18]([O-:24])[CH:19]=[CH:20][C:15]=5[C:14](=[O:25])[C:13]=2[C:22]=34)(=[O:28])=[O:29])=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2cc[n+]([O-])cc2C3=O)cc1
Reactant: CN(C)CCNN
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]nc4c3c2C(=O)c2cc[n+]([O-])cc2-4)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere a solution of N-[2-(dimethylamino)ethyl]hydrazine (0.805 g) in THF (10.75 mL) is added to a stirred suspension of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione-2-oxide of Preparative Example 21 (1.075 g) in THF (10.75 mL). After stirring for 2 h, the mixture is heated to 40° C. for 1 h. After cooling to room temperature the mixture is poured in water (150 mL) and the obtained suspension is stirred for 2 h. The precipitate is recovered by filtration and recrystallized from ethyl acetate/n-hexane to give 2-[2-(dimethylamino)ethyl)]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one-9-oxide (0.31 g).