Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br>>[Br:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCCCC(CC(=O)OC)c1ccc(O)cc1OC
Reactant: BrCCCBr
Product: CCCCC(CC(=O)OC)c1ccc(OCCCBr)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 58A) and 1,3-dibromopropane, methyl 3-[4-(3-bromopropoxy)-2-methoxyphenyl]heptanoate was obtained as an oily substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(N)cc1
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
A mixture of 1-(2-methoxyethoxy)-4-nitrobenzene (0.724 g, 3.67 mmol) and 10% Pd/C (Aldrich) (0.201 g, 1.89 mmol) in EtOH (10 mL) was evacuated under vacuum and refilled with hydrogen (4 times). The mixture was hydrogenated under balloon pressure at rt for 1.5 h. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) (eluent:EtOH) and concentrated. The crude product was purified by silica gel chromatography (25 g, eluent: EtOAc in hexanes 0%-60%) to give 4-(2-methoxyethoxy)aniline (0.548 g, 89% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 6.73-6.82 (m, 2H); 6.58-6.68 (m, 2H); 4.01-4.08 (m, 2H); 3.67-3.76 (m, 2H); 3.29-3.52 (m, 5H). m/z (ESI, +ve ion) 168.1 (M+H)+.
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][OH:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[OH:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: Nc1ccccc1CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)CC(CC(=O)OC)Nc1ccccc1CO

Procedure:
There are added in succession, to a solution of dimethyl 3-oxopentanedioate (5 g; 28.71 mmol; 4.2 ml) in dichloroethane (125 ml) at 0° C., (2-aminophenyl)methanol (2.95 g; 23.93 mol), and then NaBH(OAc)3 (6 g; 28.71 mol) in small portions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:19](=[O:20])[CH:18]=[CH:17][C:16]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:16](=[O:21])[CH:17]4[CH:18]([CH:26]5[O:25][CH:29]4[CH:28]=[CH:27]5)[C:19]3=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1=O
Reactant: c1ccoc1
Agent: [I-]
Agent: [Mg+2]
Product: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 2-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-cyclopent-4-ene-1,3-dione (248 mg, 0.78 mmol) in furan (3 ml) is added magnesium iodide (44 mg, 0.15 mmol) and the reaction allowed to stir at room temperature for 4 days. The crude reaction mixture is purified by flash chromatography to give 4-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione as a white solid (180 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].I[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23].CCOC(C)=O>CN1CCCC1=O>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Reactant: Cc1cc(O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 3-methyl-4-fluorophenol (99 mg, 0.79 mmol), potassium hydroxide (53 mg, 0.94 mmol), 4-iodo-3,5-dichloro-nitrobenzene (250 mg, 0.79 mmol) and 4A° molecular sieves (75 mg) in N-methylpyrolidinone (3 mL) was stirred at 130° C. for 2 h. The reaction mixture was poured into ice cold 1 N HCl (20 mL) and EtOAc (25 mL) was added. The EtOAc phase was separated and washed with 1N HCl (3×25 mL) and brine (25 mL). The EtOAc solution was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (Hexanes: CH2Cl2=7:3) to afford 3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-nitrobenzene (207 mg). MS Calc.: 315.0 Found: 315.0 (M).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1cncn1
Yield: 70 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 140, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (63 mg, 70%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.55 (d, 2H), 7.36-7.15 (m, 8H), 7.05-6.91 (m, 4H), 5.23 (q, 2H), 4.54-4.47 (m, 1H), 3.84-3.79 (m, 1H), 2.78-2.63 (m, 3H), 2.02-1.87 (m, 2H). MS (EI) for C28H26FN5O3. found 500.0 (MH+).
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:9]1[CH:8]=[N:7][C:6]([N:4]2[CH2:5][C:2]([F:15])([F:1])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(F)(F)C2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(F)(F)C2)nc1

Procedure:
A suspension of 0.34 g (1.58 mmol) of 2-(3,3-difluoroazetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and 8 mg of Pd/C at 10% in 10 mL of ethanol is stirred vigorously at 20° C. under 5 atm of hydrogen for 4 hours. After this time, the mixture is filtered on a Celite pad, then concentrated at reduced pressure. The resultant product is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. We thus obtain 0.188 g of the expected product in the form of a red powder, which is used as it is in the rest of the synthesis.
Reaction SMILES: Br[CH:2]([CH:4]1[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:20])[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3)[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+].CN(C)C=O>O>[N:21]([CH:2]([CH:4]1[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:20])[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3)[CH3:3])=[N+:22]=[N-:23]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)Br)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N=[N+]=[N-])O3
Yield: 72.1 %

Procedure:
A mixture of the compound obtained in Example 289 (3.30 g, 9.9 mmol), sodium azide (3.84 g, 59 mmol) and dimethylformamide (30 ml) was allowed to react at 120° C. for 4 hours. The reaction mixture was poured into water to obtain 2.13 g of the title compound as a pale brown solid (72.7%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:9].C[O:11][C:12](C)(C)[CH3:13]>C(O)C>[ClH:9].[NH2:2][C:1]([O:11][CH2:12][CH3:13])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COC(C)(C)C
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=C(N)OCC
Reaction time: 8 h

Procedure:
A solution of 226 g of ethyl cyanoacetate in 200 ml of absolute ethanol is saturated by introducing hydrochloric acid gas at 0°. The mixture is stirred at 0° overnight and then 1.5 l of tert.butyl methyl ether are added thereto. The ethyl β-amino-β-ethoxyacrylate hydrochloride which thereby precipitates is filtered off under suction, washed portionwise with 0.5 l of tert.butyl methyl ether and dried at 35° in vacuo. There is obtained ethyl β-amino-β-ethoxyacrylate hydrochloride, melting point 103°-104°.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([O:24][CH2:25][CH2:26][CH3:27])[N:16]=1.[N:28]([C@@H:31]1[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33](N2C=C(C)C(=O)NC2=O)[CH2:32]1)=[N+:29]=[N-:30]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:33]2[O:34][C@H:35]([CH2:36][OH:37])[C@@H:31]([N:28]=[N+:29]=[N-:30])[CH2:32]2)=[C:17]([O:24][CH2:25][CH2:26][CH3:27])[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCCOc1nc(N)nc2nc[nH]c12
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CCCOc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C

Procedure:
To 500 ml of an aqueous pH 6.0 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-propoxypurine (0.0985 g, 0.5 mmol) and 3'-azido-3'-deoxythymidine (0.668 g, 2.5 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 25 mL solution of trans-N-deoxyribosylase (Example 2b) at an activity of 1500 units/mL was added. The reaction was heated at 50° C. Seven days later 0.0985 g, 0.5 mmol, of 2-amino-6-propoxypurine was added to the reaction. Eleven days after the reaction was started, another 0.0985 g, 0.5 mmol, of 2-amino-6-propoxypurine was added to the reaction. The reaction was terminated after twenty-three days. The reaction was heated to 80° C. to precipitate the enzyme and then filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered, and the solvent was removed in vacuo to give a foam. The foam was chromatographed on 180 g of silica gel (230-400 mesh) eluted first with chloroform/methanol (99:1, v/v) then with chloroform/methanol (98:2, v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as an oil. The oil was dissolved in water and lyophilized to give a solid (56% yield). mp=145°-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>CCO.[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([CH:15]=[CH:14][CH:13]=2)[NH2:1])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CCCC2)c1
Yield: 70 %

Procedure:
1-(Bromomethyl)-3-nitrobenzene (51; 5 g, 23.1 mmol) was taken up in 100 mL of anhydrous THF along with pyrrolidine (2.3 mL, 27.72 mmol) and K2CO3 (4.8 g, 34.6 mmol). The reaction mixture was stirred at room temperature for 18 h and then filtered. The filtrate was concentrated under reduced pressure to afford 1-(3-nitrobenzyl)pyrrolidine 52. This material 52 was taken up in 100 mL of absolute EtOH and 10% Pd on C (300 mg) was added. The resulting reaction mixture was stirred at room temperature under 1 atm of hydrogen for 18 h. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 2.81 g of 3-(pyrrolidin-1-ylmethyl)aniline 53 (70%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.C([Li])CCC.[CH3:30][C:31]12[CH2:40][CH2:39][CH:34]([CH2:35][CH:36]1[CH:37]=O)[C:33]([CH3:42])([CH3:41])[C:32]2=[O:43].[CH2:44](Cl)[Cl:45]>O>[CH3:30][C:31]12[CH2:40][CH2:39][CH:34]([CH2:35][CH:36]1[CH:37]=[CH:44][Cl:45])[C:33]([CH3:42])([CH3:41])[C:32]2=[O:43]
Reactant: CC1(C)C(=O)C2(C)CCC1CC2C=O
Reactant: ClCCl
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: CC1(C)C(=O)C2(C)CCC1CC2C=CCl

Procedure:
A mixture of 30 g of triphenylphosphine, 200 ml of anhydrous ether and 11 g of methylene chloride is cooled to -30° and 77 ml of 1.3M n-butyl lithium solution is added over one hour. To the stirred solution is added 11 g of crude 1,3,3-trimethyl-bicyclo-(2.2.2)-octan-2-one-6-carboxaldehyde. The mixture is slowly heated to reflux and held at reflux for 2 hours. The mixture is poured into 100 ml of water and the organic layer is separated and dried over Mg 804 and the solvent is stripped off the product. Structure: ##SPC43##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)ccc1[N+](=O)[O-]

Procedure:
1.88 g of 5-methoxy-2-nitrophenol was dissolved in 20 ml of N,N-dimethylformamide. Thereafter, 1.53 g of potassium carbonate and 1.03 ml of allyl bromide were successively added to the reaction solution. After the disappearance of materials had been confirmed, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.09 g of the subject compound.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)[C:2]#[CH:3].[N:26]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)=[N+:27]=[N-:28].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[O:36]([C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH:3]=[C:2]([CH2:1][NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][CH:9]=[N:8][C:7]=2[NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:28]=[N:27]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C#CCNC(=O)c1cccnc1Nc1cc(OC)c(OC)c(OC)c1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Nc2ncccc2C(=O)NCc2cn(Cc3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.1 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 3,4,5-trimethoxyaniline (9j, 183 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide 10j as pure product. To a solution of N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide (10j, 150 mg, 0.41 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 102 mg, 0.45 mmol), in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1j (186 mg, 75%); mp: 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 1H), 8.27 (d, J=7.5, Hz, 1H), 7.85 (d, J=7.5 Hz 2H), 7.75 (brs, 1H), 7.60 (s, 1H), 7.39-7.27 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.83 (m, 7H), 6.65 (m, 1H), 5.47 (s, 2H), 4.66 (d, J=5.28 Hz, 2H), 3.85 (s, 6H), 3.81 ppm (s, 3H); MS (ESI m/z): 567 [M+H]+. Yield: 75%
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][CH:8]=C)[CH3:5])[CH3:2].[O:10]=[O+][O-].CSC.C([O-])([O-])=O.[K+].[K+]>O.CCOCC.CO>[CH2:1]([O:3][CH:4]([O:6][CH2:7][CH:8]=[O:10])[CH3:5])[CH3:2]
Reactant: C=CCOC(C)OCC
Reactant: O=[O+][O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSC
Solvent: CO
Solvent: O
Product: CCOC(C)OCC=O
Temperature: 25 °C

Procedure:
3-[1-(Ethoxy)ethoxy]-1-propene (40 g., 0.0307 mol) was stirred in 100 ml. methanol at -78° for 5.5 hours as O3 was through the solution. The resulting pale blue solution was purged with H2, dimethyl sulfide (34 ml., 43.4 g., 0.68 mol) was added, and the mixture warmed to room temperature over 45 minutes. K2CO3 (0.2 g.) was added, the reaction mixture stripped of solvent, and the residue diluted with 1:1 water:ether. The aqueous layer was separated, diluted with brine and extracted with fresh ether. The organic layers were combined, dried and stripped to yield the title product as an oil, 15.25 g., 1H-nmr: 1.24 (t, 3H), 1.37 (d, 3H), 3.50 (s, 2H), 3.61 (m, 2H), 4.81 (m, 1H), 9.87 (s, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (33.2 mg, 0.0489 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 60° C. until LC-MS showed that the starting material had been consumed (overnight). Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (24.6 mg, 90%). LRMS (APCI pos): >99% purity, 254 nm, m/e 559 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 10.33 (s, 1H), 8.42 (d, 1H), 8.25 (m, 2H), 7.97 (dd, 1H), 7.61 (m, 2H), 7.41 (d, 1H), 7.23-7.30 (m, 3H), 6.20 (d, 1H), 3.56 (m, 4H), 2.69 (m, 4H), 2.40 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.Cl>ClCCl>[NH2:23][CH:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH:2]([OH:1])[CH3:31])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1
Reactant: CC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(N)CC4)c3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Into a 50-mL round-bottom flask containing tert-butyl N-(4-[[(3R)-3-(2-hydroxypropyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate (109 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0° C. Then hydrochloric acid (12 M, 2.0 mL) was added and the resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with saturated aqueous sodium carbonate and extracted with 2×40 mL of ethyl acetate. The organic layers were combined and dried over sodium sulfate and concentrated under vacuum to give the desired 1-[(3R)-12-[(4-amino cyclohexyl)amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propan-2-ol (70 mg, crude) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:15]3([OH:22])[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([I:11])[CH:13]=4)[NH:17][C:16]3=[O:21])[C:10]=2[O:9][CH2:8]1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: Brc1cccc2c1OCO2
Product: O=C1Nc2ccc(I)cc2C1(O)c1cccc2c1OCO2
Yield: 64.8 %

Procedure:
With 2.70 g of 4-bromo-1,3-benzodioxol and 9.00 g of 5-iodoisatin as starting materials, 3.44 g of the title compound (orange color solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH3:1][N:2]([CH2:3][C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:16](=[O:18])[CH3:17]
Reactant: CNCC1(N2CCCCC2)CCCCC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)CC1(N2CCCCC2)CCCCC1

Procedure:
A mixture of 1-[1-[(methylamino)methyl]cyclohexyl]-piperidine (1.0 g., 0.005 mole) and acetic anhydride (10 ml) was heated on a steam-bath for 30 mins. The solution was evaporated to dryness and water (5 ml) was added to the residue. A saturated solution of sodium carbonate (10 ml) was added and the alkaline solution was extracted with chloroform (50 ml × 3) and dried (anhyd. Na2SO4). The chloroform solution was evaporated to dryness and the oily residue re-evaporated with ether. This was dissolved in petroleum ether (60°-80°C), treated with decol. charcoal, and filtered (hyflo). The combined filtrates were evaporated to dryness to give N-methyl-N-[(piperidino cyclohexyl)methyl]acetamide (1.3 g.).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:6]([C:16]([O:18]C(C)(C)C)=[O:17])=[N:5]1)[CH3:3].Cl>O1CCOCC1>[CH3:3][CH:2]([N:4]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:6]([C:16]([OH:18])=[O:17])=[N:5]1)[CH3:1]
Reactant: CC(C)n1nc(C(=O)OC(C)(C)C)cc1CN1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1nc(C(=O)O)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
1,1-Dimethylethyl 1-(1-methylethyl)-5-(4-morpholinylmethyl)-1H-pyrazole-3-carboxylate (101 mg) was dissolved in 1,4-Dioxane (2 ml). 4M hydrogen chloride in 1,4 dioxane (3 ml) was added and the mixture was stirred at RT under nitrogen for 6 h. The solvent was removed in vacuo, toluene (10 ml) was added and removed in vacuo to give a white solid. The solid was dried in a vacuum oven over-night to give the title compound (81 mg) as a white solid.