Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=1)[C:12]#[N:13].[Br:17]N1C(=O)CCC1=O>C(#N)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:14]([Br:17])=[CH:15][N:16]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccnc(N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
In an aluminum foil-covered flask in a darkened hood, 2-amino-isonicotinonitrile TFA salt (125 mg, 0.54 mmol) was dissolved in acetonitrile (3.5 mL). Solid N-bromosuccinimide (89.2 mg, 0.501 mmol) was added to the stirred solution in one portion at RT. The reaction solution was stirred at room temperature in darkness for 90 minutes. After evaporation of the solvent, the crude material was further purified by silica gel chromatography to give 2-amino-5-bromo-isonicotinonitrile (53 mg, 49%). LC/MS (m/z): 197.9 (MH+), Rt 2.92 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:30]=[CH:29][C:16]=2[C:17]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)[CH:30]=[CH:29][C:16]=2[C:17]2[O:18][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccccc2C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccccc3c(=O)o2)CC1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzoic acid (about 11.23 mmol) was diluted with methylene chloride (115 mL). DMF (4 drops) and pyridine (1.1 mL, 13.6 mmol) were added, followed by oxalyl chloride (1.1 mL, 12.6 mmol). A precipitate formed immediately. After 2 hours, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue from the filtrate concentration was purified by flash column chromatography (5% EtOAc/CH2Cl2) to give the desired product (4.83 g, 9.82 mmol, 87%) as a yellow solid.
Reaction SMILES: N#N.[Cl:3][CH2:4][CH2:5]O.Cl[S:8]([OH:11])(=[O:10])=[O:9].[OH-:12].[Na+:13]>CO.C(Cl)(Cl)Cl>[S:8]([O-:11])([O-:12])(=[O:10])=[O:9].[Cl:3][CH2:4][CH3:5].[Na+:13].[Na+:13]
Reactant: [OH-]
Reactant: O=S(=O)(O)Cl
Reactant: OCCCl
Agent: N#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCl
Product: O=S(=O)([O-])[O-]
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A 2 liter round bottom flask was equipped with an overhead stirrer, thermometer, condenser and addition funnel with N2 lnlet. 216 g of 2-chloroethanol and 550 cc of dry chloroform were charged to the flask and chilled to -30° C. Chlorosulfonic acid was added dropwise in one hour, and the reaction was allowed to warm to room temperature and stir for 11/2 hours. With the reaction solution again at -30° C., cold methanol was added dropwise followed by 300 g of 50% NaOH solution. The reaction was heated to reflux and filtered hot. The filtrate crystallized upon standing yielding white crystals, which were filtered and washed with cold methanol to yield sodium 2-chloroethane sulfate.
Reaction SMILES: C(O[CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2.C1(C)C=CC=CC=1.[Cl-].C([Al+]CC)C>C(#N)C>[Si:12]([O:11][CH2:10][C@H:8]1[S:9][CH:5]([N:34]2[CH:33]=[N:32][C:31]3[C:35]2=[N:36][CH:37]=[N:38][C:30]=3[Cl:29])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 10 (0.43 g, 1.04 mmol) and 6-chloropurine (0.24 g, 1.56 mmol) in 17 mL acetonitrile was cooled to 0° C. and a 1.8M toluene solution of diethylaluminum chloride (0.59 mL, 1.06 mmol) was added over 1 minute. Stirring was continued at 0° C. for 5 minutes and at 25° C. for 10 minutes. The reaction mixture was quenched by pouring into a mixture of 20 mL dichloromethane and 10 mL saturated NaHCO3. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was flash chromatographed with 9:1 -hexane/ethyl acetate followed by 4:1 -hexane/ethyl acetate. Solvent removal gave a 1:1 α/β anomeric mixture: yield 0.315 g (59%); FAB MS 509 (M+H)+ ; 1H NMR (CDCl3) of β anomer, δ 8.7 (s, 1, H-2), 8.45 (s, 1, H-8), 7.7 (m, 4, ArH), 7.4 (m, 6, ArH), 6.27 (m, 1, 7'-H), 3.95 (m, 1, 5'-H), 3.85 (m, 2, 4'-H, 5'-H), 2.45 (m, 2, 2'-H's), 2.25 (m, 1, 3'-H), 1.85 (m, 1, 3'-H), 1.1 (s, 9, t-butyl).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[C:34]=4[CH3:43])(=[O:40])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(Cl)c4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-2-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=610.1)=80%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17])([O-])=O.N>O.C(O)C.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCCC(=O)Nc1n[nH]c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g of iron sulphate heptahydrate dissolved in 50 cm3 of hot water are added to a solution of 2.05 g of N-[5-nitro-1H-indazol-3-yl]butanamide, described in Example 23, in 80 cm3 of ethanol; the mixture is stirred for 30 minutes at room temperature, 24 cm3 of 28% aqueous ammonia are added and the mixture is then refluxed for 2 hours, 10 cm3 of 28% aqueous ammonia are added and the mixture is stirred for a further 10 minutes. The precipitate is filtered off while hot, on a sinter funnel packed with Celite, rinsed with methanol until the filtrate is colourless, and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and is washed with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After drying (90 Pa; 50° C.) 870 mg of N-(5-amino-1H-indazol-3-yl)butanamide are obtained in the form of a purple powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=2[OH:40])[N:23]=1>C(Cl)Cl>[F:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:40])[C:33]=1[C:24]1[N:23]=[C:22]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h

Procedure:
A solution of tert-butyl(R)-pyrrolidin-3-ylcarbamate (368 mg, 1.97 mmol) and triethylamine (0.46 mL, 3.28 mmol) in CH2Cl2 was rapidly added to a stirring solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (475 mg, 1.65 mmol) in 15 mL CH2Cl2 at 0° C. under an N2 atmosphere. The reaction was stirred for 1 h before it was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 yielded tert-butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 439.5 (M+H)+ at 2.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].CN(C=O)C.O>C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(CCl)OCC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 23.3 %

Procedure:
Chloroacetaldehyde diethyl acetal (1.9 g), potassium benzoate (2.0 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (60 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration and separation, the organic layer was concentrated and thereby yielded the target compound (0.69 g) in a yield of 30%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(O)c1

Procedure:
To a solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 32.8 mmol) in MeOH (100 mL) cc H2SO4 (1 mL) is added. The solution is refluxed for 14 h, then concentrated to about 30 mL and poured into water. The aqueous layer is extracted with ether (50 mL×4) and the combined organic extracts are neutralized with a saturated aqueous solution of NaHCO3 (50 mL×2), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder. TLC, Rf (hexane/AcOEt 2:1 )=0.55. 1H-NMR (CDCl3, 300 MHz): δ=2.3 (s, 3H), 3.9 (s, 3H), 7.15 (d, 1H), 7.5 (d, 1H), 7.6 (s, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]2[O:3][C:2]([CH3:1])([C:16]#[C:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:7][CH2:6][C:5]=2[C:8]=1[CH3:15])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#Cc1ccccc1)O2

Procedure:
A mixture of 0.3 g of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-(phenylethynyl)-2H-1-benzopyran-6-ol, 7 ml of pyridine and 0.5 ml of acetic anhydride was allowed to sit at room temperature over night. The reagents were evaporated under reduced pressure, at the end azeotropically with toluene. The residue was crystallized from hexane to give 0.21 g of colorless crystals with m.p. 123°-125°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:17][CH:18]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:17][CH:18]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)nc1
Reaction time: 16 h
Yield: 71.9 %

Procedure:
Pd(OH)2 (20% 77 mg) was flame dried under vacuum and was added to a solution of 5-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine (286.4 mg, 0.6714 mmol) in acetic acid (50 mL). The mixture was hydrogenated on a Parr shaker at 50 psi and at 50° C. for 16 h. The catalyst was filtered off with the aid of celite and the acetic acid was removed in vacuo. 1H NMR indicated that the reaction was incomplete and the residue was resubjected to the reaction conditions (50 psi and 60° C.) for an additional 6 h. The catalyst was removed via filtration through celite and the solvent was removed in vacuo. Radial chromatography (solvent gradient, CH2Cl2 to 10% MeOH in CH2Cl2) provided the desired material (207 mg, 72%). 1H NMR (250 MHz, CDCl3): δ 7.19 (m, 4H), 6.84 (m, 3H), 6.75 (d, J=2.4 Hz, 1H), 6.68 (dd, J=2.4, 8.4 Hz, 1H), 6.59 (dd, J=2.4, 8.4 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 4.21 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 3.38 (m, 1H), 3.06 (m, 2H), 2.90 (t, J=5.7 H 2.69 (m, 4H), 2.11 (m, 2H), 1.84 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:24][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[N:10]([CH2:21][CH3:22])[C:9](=[O:23])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(Br)c(OC)cc21
Yield: 77.1 %

Procedure:
A solution of 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3.38 g, 10.58 mmol) and N-bromosuccinimide (2.072 g, 11.64 mmol) in acetic acid (2.5 mL) and chloroform (25 mL) was heated at reflux for 2 hrs. The reaction mixture was diluted with chloroform (25 mL), washed with saturated aqueous solution of NaHCO3 and water, dried over Na2SO4, filtered and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel column eluted with EtOAc/hexane (3:7) provided the desired compound (3.25 g, 77%) as white powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]([O:17][CH2:18][N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH:29]C(=O)C)=[N:23][C:24]=2[OH:28])[CH2:8][O:9]CC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].C1CCCCC=1>[Pd].C(O)C>[NH2:29][C:22]1[N:21]=[C:20]2[C:25]([N:26]=[CH:27][N:19]2[CH2:18][O:17][CH:7]([CH2:8][OH:9])[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:24]([OH:28])[N:23]=1
Reactant: CCCCOCC(COCc1ccccc1)OCn1cnc2c(O)nc(NC(C)=O)nc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCOCC(CO)OCn1cnc2c(O)nc(N)nc21
Reaction time: 36 h
Yield: 8.7 %

Procedure:
A mixture of N-[9-[[1-(butoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-6-hydroxy-9H-purin-2-yl]acetamide (1.15 g, 25.9 mmol), 20% palladium on carbon (0.2 g), cyclohexene (20 ml), and ethanol (10 ml) is heated at reflux under N2. After 8 and 20 hours, additional amounts of catalyst (0.1 g) are added. After 36 hours, the solution is cooled, filtered through celite, and the filter cake is washed with DMF/ethanol. The filtrates are combined, refiltered and concentrated. The residue is mixed with aq. methyl amine (20 ml) and the mixture is heated at reflux for two hours, filtered and concentrated. The residue is recrystallized from water to give the desired product (0.7 g), mp 208°-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:21][NH2:22].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[O:29]=[C:28]1[NH:22][CH2:21][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH2:9]3)[CH:4]=2)[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(CN)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CNC(=O)N3)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
To a solution of compound 17 (1.38 g, 4.5 mmol) in THF (20 mL) at room temperature was CDI (0.80 g, 4.95 mmol) and the reaction was stirred at 80° C. for 6 hr. The mixture was cooled to room temperature and the solid formed was filtered, washed with diethyl ether to afford 0.99 g (72%) of compound 10 as an off-white foam. IR (KBr) vmax. cm−1: 3210, 3162 (NH), 3032 (Ar—H), 1691 (C═O), 1607, 1515, 1419 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.47 (s, 9H, (CH3)3C); 3.06 (m, 4H, 2CH2); 3.52 (m, 4H, 2CH2); 4.49 (s, 2H, CH2); 6.69 (m, 2H, aromatic-H), 6.74 (m, 1H, aromatic-H); 7.82 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=28.60 (CH3)3C), 43.35 (CH2), 43.90 (CH2), 50.66 (CH2), 80.10 (CH3)3C), 112.11 (aromatic-C), 112.28 (aromatic-C), 117.19 (aromatic-C), 130.18 (aromatic-C), 134.88 (aromatic-C), 143.18 (aromatic-C), 154.62 (CO), 155.93 (C═O). Calculated (%) for C17H24N4O3 (332.18); C, 61.43; H, 7.28; N, 16.86. found (%) C, 61.38; H, 7.32; N, 16.81.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[CH:10]([NH:29]C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:28])[NH:26][OH:27])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:39]>>[ClH:39].[CH2:1]([O:8][C:9](=[O:37])[CH:10]([NH2:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:28])[NH:26][OH:27])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)OCc1ccccc1
Reactant: ClCCl
Product: Cl
Product: NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
The hydroxamate 5 (0.4 g) was dissolved in CH2Cl2 and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 6 as a white amorphous solid (0.25 g, 71.4%). 1H NMR (DMSO-d6): 11.18 (s, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.31-7.39 (m, 5H), 7.24 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 5.19 (s, 2H), 4.40 (m, 1H), 3.07-3.18 (m, 2H) LCMS (m/e): Obsd, 407.0; Calcd, 406.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:31][CH2:32][CH2:33]O)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.CCN(CC)CC.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:31][CH2:32][CH2:33][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: OCCOc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2c(-c3ccc(Cl)cc3Cl)nc3c(cnn3-c3ccccc3)c2OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethanol (13 mg, 0.025 mmol, prepared in 84% yield as described in Example 5 except using ethylene glycol as solvent.) in anhydrous CH2Cl2 (0.5 mL) is added CH3SO2Cl (5 μL) followed by Et3N (20 μL). After the addition, the mixture is stirred at room temperature for 2 h. and morpholine (20 μL) is added. After the resulted mixture is stirred at 60° C. for 10 h. it is cooled down to room temperature and treated with water (4 mL) and extracted with EtOAc (3×3 mL). The organic layers are combined and concentrated. The residue is purified by preparative LC/MS to provide the titled compound 5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine. HPLC-MS calculated for C30H25Cl3N4O2 (M+H+): 579.1. Found: 579.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH:33]1([NH2:43])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:43][CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1)=[O:31]
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)NC2CCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:23][C:24]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1)=[CH2:24]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Yield: 85 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-spiro [cyclopropane-1,3′-indolin]-2′-one (802 mg, 2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (462 mg, 3 mmol) in a 20 mL microwave vial was added PhCH3/EtOH (8 mL/4 mL), followed by 1 M Na2CO3 (3 mL, 3 mmol) and Ph(PPh3)4 (46 mg, 0.04 mmol, 2 mol %) was added and the resulting mixture was purged with argon, then microwaved 3 h at 120° C. After aqueous workup, the solution was extracted with EtOAc and was purified by flash chromatography (Hex/EtOAc 1:1) to give the crude title compound as a light yellow foam (512 mg) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.10-6.88 (m, 5H), 6.54 (t, J=7.4 Hz, 1H), 6.06 (d, J=18.0 Hz, 1H), 5.92 (d, J=7.6 Hz, 1H), 5.49 (d, J=7.6 Hz, 1H), 3.46 (d, J=8.2 Hz, 1H), 2.30-2.18 (m, 2H); MS ESI 302.0 [M+H]+, calcd for [C19H15N3O+H]+ 302.1.