Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]=C)[C:9]#[N:10])=[CH:4][CH:3]=1.CC(C)=[O:16].O>O.O=[Os](=O)(=O)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]=[O:16])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: C=CCC(C#N)c1ccc(I)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: N#CC(CC=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-iodo-phenyl)-pent-4-enenitrile (2.8 g, 9.9 mmol, intermediate for preparing EXAMPLE 2), OsO4 (0.7 mL, 4% in water, 0.10 mmol), and NaIO4 (4.44 g, 20.8 mmol) in 2:1 acetone/H2O (100 mL) was stirred at room temperature for 16 h. TLC (1:1 hexanes/EtOAc) showed no starting material left. The mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (50 mL×4). The organic layer was washed with brine, dried (Na2SO4) and concentrated by rotary evaporation. Purification by silica gel chromatography (1:1 hexanes/EtOAc) gave 2-(4-iodo-phenyl)-4-oxo-butyronitrile as a yellowish oil, 1.9 g (68%). 1H NMR (300 MHz, CDCl3): δ 9.85 (s, 1H), 7.84 (d, 2H), 7.24 (d, 2H), 4.44 (t, 1H), 3.33 (dd, 1H), 3.14 (dd, 1H).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:8][C:9]([CH3:29])=[CH:10][CH2:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[CH2:15][CH2:16]/[C:17](/[CH3:27])=[CH:18]/[CH2:19][S:20][CH2:21][C@H:22]([NH2:26])[C:23]([OH:25])=[O:24].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH:1]1([S:4]([NH:26][C@@H:22]([CH2:21][S:20][CH2:19]/[CH:18]=[C:17](\[CH3:27])/[CH2:16][CH2:15]/[CH:14]=[C:13](\[CH3:28])/[CH2:12][CH2:11][CH:10]=[C:9]([CH3:29])[CH3:8])[C:23]([OH:25])=[O:24])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NS(=O)(=O)C1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, to a suspension of cyclopropanesulfonyl chloride (169 mg, 1.2 mmol) and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) dropwise. The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (60 mL) and washed by 0.5 N HCl (10 mL×1), H2O (10 mL×2) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was then further purified by preparative HPLC (50 mg, 12%) to yield Compound N-79. 1H-NMR (500 MHz, CD3OD): δ 0.86-0.89 (m, 2H), 0.93-0.96 (m, 2H), 1.50 (s, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 1.61 (s, 3H), 1.86-1.89 (m, 2H), 1.95-1.98 (m, 4H), 2.00-2.04 (m, 2H), 2.43-2.46 (m, 1H), 2.66-2.68 (m, 1H), 2.76-2.79 (m, 1H), 3.09-3.13 (m, 1H), 3.16-3.21 (m, 1H), 4.02 (t, J=5.0 Hz, 1H), 4.99-5.01 (m, 2H), 5.15 (t, J=5.0 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 5.58, 6.28, 16.16, 16.30, 17.81, 25.96, 27.39, 27.80, 30.41, 31.73, 34.88, 40.79, 40.90, 57.75, 121.67, 125.17, 125.47, 132.12, 136.28, 140.55, 174.39; ES-MS: mass calcd for Chemical Formula: C21H35NO4S2 429.64. Found (M+) m/z 430.2, (M+Na) m/z 452.2.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][CH:7]=[CH:6]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>Br(O)(=O)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc2cccnc2cc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Product: Cc1cc2ncccc2cc1O
Temperature: 25 °C
Yield: 47.2 %

Procedure:
6-Methoxy-7-methyl-quinoline (3 g) was added to an aqueous bromic acid solution (30 ml), and the mixture was heated under reflux for 7 hr. The reaction solution was cooled to room temperature, the aqueous layer was then neutralized with an aqueous sodium hydroxide solution and an aqueous sodium hydrogencarbonate solution. The organic layer was extracted with ether, the solvent was removed by distillation under the reduced pressure, and the residue was washed with cooled ether to give 6-hydroxy-7-methylquinoline (1.3 g, yield 47%).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.[O:15]=[C:16]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:34][C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:17]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)[O:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]1=[O:15])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Agent: FB(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of triethyl orthoformate (71 mL, 0.43 mol)] in dichloromethane (250 mL) at −10° C. under nitrogen was added boron trifluoride diethyletherate (54 mL, 0.43 mol) dropwise over 30 minutes. The mixture was allowed to warm to 0° C. and stirring was continued at 0° C. for 15 minutes. The mixture was then cooled to −78° C. and a solution of benzyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (50 g, 0.14 mol) in dichloromethane (250 mL) was added dropwise over 1 hour, followed by N-ethyl-N-isopropylpropan-2-amine (87 mL, 0.50 mol) over 1 hour at −78° C. The mixture was continued to stir at −78° C. for 30 minutes and then at 25° C. for 15 hours. The reaction mixture was diluted with dichloromethane (750 mL) and then partitioned with saturated sodium bicarbonate solution (500 mL). The organic phase was washed with water (500 mL), saturated sodium chloride solution (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-50% ethyl acetate in hexane) afforded benzyl 3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (50 g, 78%) as a yellow oil. ESI-MS m/z calc. 453.2. found 408.5 (M+1-OEt)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][CH:9]=[C:10]([N+:28]([O-:30])=[O:29])[CH:11]=3)[N:16]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH2:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COCCON1CN=C(Nc2ccc(Cl)cc2F)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6 nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallized from methylene chloride/isohexane to give 4-(4-chloro-2-fluoroanilino)-1-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:22][CH2:23][OH:24]>C(O)C.O>[OH:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: OCCCl
Reactant: O=C(c1ccc(O)cc1)c1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(OCCO)cc1)c1c[nH]c2ccccc12

Procedure:
7 g of 3-(p-hydroxybenzoyl)indole and 1.44 g of sodium hydroxide were dissolved in 200 ml of a mixture of ethanol and water (ethanol:water=1:1). 2.85 g of 2-chloroethanol was added to the solution followed by reflux for 3 hours in oil bath. The solvent was evaporated to dryness and the residue was extracted with water-ethyl acetate. The organic layer obtained was purified by column chromatography on silica gel to give a crude product. It was recrystallized from ethyl acetate to obtain 3-[p-(2-hydroxyethoxy)benzoyl]indole (compound 15) in the form of white needle crystals. (Yield: 54%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CS(C)=O.O>[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][C:1]#[N:2])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CN(Cc2ccccc2)CCO1

Procedure:
A mixture of finely ground sodium cyanide (39.6 g.) and 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (144.4 g.) in dimethyl sulphoxide (600 ml.) is stirred and heated at 60°-65° C. for 3.5 hours. The mixture is cooled, diluted with water (6 l.) and extracted with ether (3 × 2 l.). The ether extracts are combined and washed with brine (2 × 1 l.) and dried over anhydrous magnesium sulphate and the solvent removed by evaporation in vacuo. The residue is recrystallised from petroleum ether (b.p. 40°-60° C.) to give 4-benzyl-2-cyanomethylmorpholine, m.p. 62° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1N.N(OCCC(C)C)=O.[CH3:19][S:20]SC>>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[S:20][CH3:19]
Reactant: CSSC
Reactant: Nc1c(F)cc(F)cc1Br
Agent: CC(C)CCON=O
Product: CSc1c(F)cc(F)cc1Br
Temperature: 75 °C
Yield: 66 %

Procedure:
Dissolve 2-bromo-4,6-difluoroaniline (40 g, 192 mmol) in methyldisulfide (250 mL) and heat to 75° C. under nitrogen. Add isoamyl nitrite (67 mL, 500 mmol) dropwise via an addition funnel trough a reflux condenser (˜1 drop/sec). Large exotherm may occur if addition is too fast. After addition is complete, heat the reaction to 95° C. for 1 hour and cool to room temperature and concentrate in vacuo. Purify dark brown residue via silica gel chromatography eluting with hexanes to yield 30.3 g of 1-bromo-3,5-difluoro-2-methylsulfanyl-benzene (66%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([OH:26])[C@@H:21]1[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([O:26][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)[C@@H:21]1[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](F)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a stirring solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-2-((tert-butyldiphenylsilyloxy)methyl)-3-fluoro-5-hydroxycyclopentyl)hept-5-enoate (prepared in Step D, 28.6 g, 52.8 mmol) in anhydrous DCM (500 mL) was added dihydropyran (6.69 g, 79.3 mmol). The reaction mixture was cooled to 0° C. and p-toluenesulfonic acid (25 mg) was subsequently added and the reaction was stirred for 2 hours at 0° C. The reaction mixture was then allowed to warm to room temperature and stirring was continued for another 2 hours. The crude reaction mixture was transferred to a separatory funnel, washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic phase was dried over sodium sulfate, filtered, and the solvents were removed by evaporation to afford the crude title intermediate (32.7 g). The crude intermediate was carried on with no further purification.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][CH:34](O)[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1F)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1ccccc1F)O2

Procedure:
2-(2-Fluorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 800 mg of 2-(2-fluorophenyl)chroman-4,6diol. 1H NMR (300 MHz, d6-DMSO) δ: 7.50 (m, 1H), 7.39 (m, 1H), 7.26-7.19 (m, 2H), 6.63 (m, 1H), 6.53-6.50 (m, 2H), 5.21 (dd, 1H, J, 10.2, 2.3 Hz), 2.98 (ddd, 1H, J −16.9, 11.2, 6.0 Hz), 2.66 (ddd, 1H, J −16.9, 5.0, 2.9 Hz), 2.11 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[NH2:15])(=[O:4])[CH3:3].[N:16]#[C:17][NH2:18]>O.Cl>[C:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[NH:15][C:17]([NH2:18])=[NH:16])(=[O:4])[CH3:3]
Reactant: N#CN
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 157.5 %

Procedure:
A mixture of 108 (100 mg, 0.43 mmol) and cyanamide (27 mg, 0.65 mmol) was mixed and heated at 85-100 C. with stirring for 15 minutes. The liquid mass was cooled to room temperature, dissolved in hot water (0.7 mL), and acidified with 1-2 drops of conc. HCl. The thick solid which separated was filtered and dried to give crude 113 (160 mg). This was recrystallized from 5% HCl to give the pure hydrochloride salt of 113 (50 mg, 52%): mp 284-287 C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH:25]([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH:25]([C:10]1[CH:11]=[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH:13]=[CH:14][C:9]=1[OH:8])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: CCOc1ccc(Oc2ccc(OCc3ccccc3)c(C(C)C)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(Oc2ccc(O)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
Then, 4.4 g of 4-(4-ethoxyphenoxy)-2-isopropylphenyl benzyl ether and 100 ml of ethyl acetate were charged into a reaction vessel, and air in the vessel was replaced with nitrogen. Then, 0.50 g of 5% palladium-carbon was added, and nitrogen in the vessel was replaced with hydrogen, followed by vigorous stirring at room temperature for 24 hours. After hydrogen in the vessel was replaced with nitrogen, the reaction vessel was filtered with Celite, and the flitrate was concentrated. The residue was subjected to silica gel chromatography to give 3.1 g of 2-isopropyl-4-(4-ethoxyphenoxy)phenol (yield, 93%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9](Cl)([CH3:11])=[O:10].CCN(C(C)C)C(C)C.C(Cl)Cl>[Pd].CCO>[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][CH3:1])[CH2:4]1)(=[O:10])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CNC1CCCNC1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CNC1CCCN(C(C)=O)C1

Procedure:
1-Acetyl-3-(methylamino)piperidine was prepared from N3-Cbz protected 3-methylamino-piperidine: i) AcCl, i-Pr2NEt, CH2Cl2; ii) H2 (1 atm), 10% Pd/C, EtOH. 1H-NMR (CD3OD): δ (ppm) 4.0 (m, 1H), 3.6 (m, 1H), 3.4-3.2 (m, 2H), 3.0 (m, 1H), 2.6 (s, 3H), 2.1 (s, 3H), 1.8-1.6 (m, 4H).
Reaction SMILES: [N:1]([S:4]([C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:6])=[O:5])=[C:2]=[O:3].[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=1>ClCCl>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([S:4]([NH:1][C:2]([NH:28][C:23]2[N:22]=[C:21]([O:20][CH3:19])[N:26]=[C:25]([CH3:27])[N:24]=2)=[O:3])(=[O:6])=[O:5])[CH:16]=1
Reactant: COC(=O)c1ccc(OC)cc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 119 g of the compound of Example 6 in 100 ml dichloromethane was added over 0.25 hours to a suspension of 57 g of 4-methoxy-6-methyl-1,3,5-triazin-2-amine in 1000 ml dichloromethane. The reaction was heated at reflux for 3 to 4 hours, then stirred overnight at ambient temperature. The reaction mixture was filtered and dried. The crude product was dissolved in 2000 ml boiling dichloromethane, the solution filtered, and the filtrate evaporated in vacuo to give 75 g of the title compound, m.p. 183°-186° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C[N:12]([CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:22][CH2:23]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CN(CC1CCNCC1)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Yield: 81.4 %

Procedure:
A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (0.2 g, 1.23 mmol), tert-butyl methyl(piperidin-4-ylmethyl)carbamate (0.29 g, 1.36 mmol) and DIPEA (1 mL, 5.7 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (40% EtOAc/isohexane) to give tert-butyl (1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a yellow oil (0.34 g, 80%). To a solution of this oil (0.15 mg, 0.44 mmol) in DMF (5 mL) cooled to 0° C. was added sodium hydride (27 mg, 0.66 mmol, 60% in mineral oil) and the mixture was stirred at 0° C. for 15 min. Iodomethane (0.03 mL, 0.53 mmol) was added and the mixture was stirred at 0° C. for 30 min. Additional sodium hydride (14 mg, 0.33 mmol) and iodomethane (0.02 mL, 0.78 mmol) were added, the reaction mixture was allowed to warm to 10° C. and stirred for 1 hr. Water (10 mL) was added and the mixture was extracted with EtOAc (60 mL). The organic layer was washed with water (7×10 mL), washed with brine (10 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue by silica gel column chromatography (30% EtOAc/isohexane) afforded tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate as a yellow oil (148 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 3.74 (s, 3H), 3.38-3.26 (m, 2H), 3.25-3.15 (m, 2H), 3.12-2.95 (m, 2H), 2.89 (s, 3H), 1.90-1.71 (m, 3H), 1.60-1.32 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: C(N[C:6]([C:8]1[N:9]=[C:10]2[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:11]2=[N:12][C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])CCC.[OH-:24].[Na+]>C(O)C>[CH2:15]([NH:14][C:13]1[N:12]=[C:11]2[N:19]([CH2:22][CH3:23])[N:20]=[CH:21][C:10]2=[N:9][C:8]=1[C:6]([OH:7])=[O:24])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCNC(=O)c1nc2cnn(CC)c2nc1NCCCC
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCNc1nc2c(cnn2CC)nc1C(=O)O

Procedure:
23.5 g. of N-butyl-6-butylamino-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide (0.0735 mol.) suspended in 230 ml. of sodium hydroxide (2.5 N) and 460 ml. of ethanol are heated at reflux for 48 hours. Then the solution is evaporated to a volume of about 60-80 ml. The sodium salt of the acid precipitates. Acidification of the pulp with dilute hydrochloric acid with stirring provides 6-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid which is filtered off, washed with water and dried at 75°, yield 17.7 g. (91%), m.p., 97°-98° (hexane). The ester is prepared by reacting the foregoing acid with alcoholic hydrochloric acid at room temperature for 4 days. After this period, the ethanol is evaporated, the residue treated with dilute ammonia in order to remove unreacted acid and then dried at 40°. Recrystallization from ligroin yields 6-butylamino-1-ethyl-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid ethyl ester, m.p. 64.5°-65.5°.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:19]([O-:21])=[O:20])[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O.[S]>>[OH:23][C:7]1[C:8]2[C:9](=[O:22])[C:10]3[C:15](=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=[CH:12][CH:11]=3)[C:16](=[O:18])[C:17]=2[C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Product: Nc1ccc(O)c2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
100 parts of 1,8-dinitroanthraquinone are added to a reaction mixture prepared from 1,000 parts of 20% strength oleum and 25 parts of boric acid. 15 parts of sulphur are then added at room temperature in the course of 25 minutes, and the reaction mixture is warmed to 60° C. and maintained at this temperature with stirring for 4 hours. After cooling down, the reaction product is precipitated out by the dropwise addition of 158 parts of 78% strength sulphuric acid and 500 parts of water, in each case with cooling, and isolated as indicated in Example 1. 61.6 parts of 1-hydroxy-4-amino-5-nitroanthraquinone are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: CCN=C=O
Reactant: Cc1cnc(-c2cc(F)ccc2F)nc1Nc1ccnc2cn[nH]c12
Solvent: c1ccncc1
Solvent: CC#N
Product: CCNC(=O)n1ncc2nccc(Nc3nc(-c4cc(F)ccc4F)ncc3C)c21
Temperature: 70 °C

Procedure:
To N-(2-(2,5-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (108 mg, 0.319 mmol) suspended in acetonitrile (3.2 mL) was added isocyanatoethane (125.3 μl, 1.60 mmol), 15 drops of pyridine and the mixture was heated at 70° C. overnight. The reaction was cooled to give a solid which was collected by filtration, rinsed with a acetonitrile, and dried under high vacuum to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (3H, t, J=7.20 Hz) 2.43 (3H, s) 3.37-3.48 (2H, m) 7.36-7.51 (2H, m) 7.85 (1H, ddd, J=9.22, 5.94, 3.03 Hz) 8.47-8.57 (1H, m) 8.65 (1H, s) 9.06 (1H, d, J=5.30 Hz) 9.13 (1H, t, J=5.94 Hz) 12.07 (1H, s). MS [M+H] found 410.4.