Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][C:31]=1[C:42]([OH:44])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:42]([C:31]3[CH:32]=[C:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:34]=[CH:35][C:30]=3[O:29][CH3:28])=[O:44])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccccc2)cc1C(=O)O
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: COc1ccc(-c2ccccc2)cc1C(=O)N(C)[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 78 and 4-methoxybiphenyl-3-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:20][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: Cc1cccc2c1C=Cc1ccccc1C2O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc2c1C=Cc1ccccc1C2Cl

Procedure:
23 g. of 5-Hydroxy-1-methyl-5H-dibenzo[a,d]cycloheptene in 200 ml. of absolute benzene are heated with 45 ml. of thionylchloride for two hours under reflux conditions. The mixture is subsequently evaporated under reduced pressure. The resulting, white crystalline residue is recrystallized from carbon tetrachloride. 5-Chloro-1-methyl-5H-dibenzo[a,d]cycloheptene, melting at 158°-160°C., is obtained.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:31])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:31])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23]([O:29][CH3:30])=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CCl)c2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(=O)CCl)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of N-((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (180 mg, 0.401 mmol) in DCM (3 mL) was added Dess-Martin periodinane (204 mg, 0.481 mmol). The reaction was stirred at ambient temperature for 3 hours, then purified directly by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the desired product as a white foamy solid (114 mg, 64% yield). MS (apci) m/z=447.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1ccccc1F
Product: O=C(Cl)CCCc1ccccc1F
Yield: 99.8 %

Procedure:
A mixture of 4-(2-fluorophenyl)butyric acid (100 g, 0.55 mol) and thionyl chloride (418.8 g, 3.51 mol) was refluxed for 3 h. The excess thionyl chloride was removed in vacuo to give 110.1 g (100%) of 4-(2-fluorophenyl)butyryl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH:27]([NH2:30])([CH3:29])[CH3:28]>C(Cl)Cl.O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:7]
Reactant: CC(C)N
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(=O)NC(C)C)c1[N+](=O)[O-]
Yield: 80.2 %

Procedure:
A solution of 3-methyl-2-nitrobenzoic acid (2.00 g, 11.0 mmol) and triethylamine (1.22 g, 12.1 mmol) in 25 mL of methylene chloride was cooled to 10° C. Ethyl chloroformate was carefully added and a solid precipitate formed. After stirring for 30 minutes isopropylamine (0.94 g, 16.0 mmol) was added and a homogeneous solution resulted. The reaction was stirred for an additional hour, poured into water and extracted with ethyl acetate. The organic enacts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure to afford 1.96 g of the desired intermediate as a white solid melting at 126-128° C.
Reaction SMILES: C(O)(=O)C.O.CN1CCCC1=O.[Cl:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][C:17]([N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[C:16]([F:34])[CH:15]=1>[Fe].O1CCCC1>[NH2:20][C:19]1[C:14]([Cl:13])=[CH:15][C:16]([F:34])=[C:17]([N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])[CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Nc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 45 g of iron powder, 9 ml of acetic acid, and 36 ml of water was heated at 100° C. for 0.5 hour under stirring for activation. To the mixture was added 150 ml of N-methylpyrrolidone. The external temperature was set at 80° C., and 57.2 g of N-(4-chloro-2-fluoro-5-nitrophenyl)phthalimide was added thereto in small portions under stirring (reaction temperature: 85 to 95° C.). After completion of the addition, the stirring was continued at the same temperature for an additional 1 hour period. While the reaction mixture was warm, tetrahydrofuran was added thereto, followed by allowing the mixture to cool. Any insoluble matter was separated by Celite filtration, and the filtrate was concentrated under reduced pressure. Water was added to the concentrate, and the precipitated solid was collected by filtration. The resulting solid was washed successively with water and methanol and dried under reduced pressure to give 48.6 g of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[O:10][CH2:11][CH2:12][N:13]([C:17](=O)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH:29]=[CH:28][N:27]=[CH:26]5)=[CH:21][CH:20]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[O:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH:29]=[CH:28][N:27]=[CH:26]5)=[CH:23][CH:24]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cc1ccc(-n2ccnc2)cc1)N1CCOc2ccc(-n3ccnc3)cc2OCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1cn(-c2ccc(CCN3CCOc4ccc(-n5ccnc5)cc4OCC3)cc2)cn1

Procedure:
In a manner similar to example 8, react 9-(1H-imidazol-1-yl)-4-[2-[4-(1H-imidazol-1-yl)phenyl]acetyl]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:34]=2[C:35]#[N:36])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCCCN
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCCCNc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation of R, 1.1 g, 4.163 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (0.807 g, 6.245 mmol) followed by 2-(4-aminobutoxy)-4-nitrobenzonitrile (Preparation O, 1.174 g, 4.99 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, with 50% ethyl acetate in pet-ether) to get 2-(4-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)butoxy)-4-nitrobenzonitrile (0.9 g, 47%) as a light yellow solid. LC-MS (M+H)+=464.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (1H, d, J=8.4 Hz), 7.98 (1H, s), 7.91 (1H, d, J=8.8 Hz), 7.57 (1H, m), 7.32-7.13 (5H, m), 4.39-4.35 (2H, t, J=6.4 Hz), 4.19-4.15 (1H, t, J=8.0 Hz), 3.46-3.33 (2H, m), 2.85-2.75 (1H, m), 2.60-2.50 (2H, m), 1.99-1.00 (1H, m), 1.88-1.75 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].CC([O-])(C)C.[K+].C(O)(=O)C>C1COCC1.O.C([O-])(O)=O.[Na+]>[C:16]1([S:13]([CH2:12][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N+:8]([O-:10])=[O:9])(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1CS(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
To a stirred solution of 1-bromo-4-nitrobenzene (5.05 g, 25 mmol) and chloromethyl-phenylsulfone (4.76 g, 25 mmol) in dry THF (50 mL) at −65° C. under nitrogen is added 1.0M KOtBu in THF (55 mL, 55 mmol). The deep purple reaction is allowed to warm to 0° C. over 1.5 hours and then treated with glacial acetic acid (4 mL). The reaction is diluted with water (100 mL) and saturated aqueous NaHCO3 (100 mL), and then extracted with CH2Cl2 (2×200 mL). The extracts are dried (MgSO4) and concentrated in vacuo to a light orange solid. Trituration with ethyl acetate and hexanes affords the title compound as a pale yellow solid (6.45 g, 72%). Mp: 143-144° C. MS (ES−): 354 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(C)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1F

Procedure:
41.7 g (297.54 mmol) of 2-fluoro-5-methylanisole is refluxed overnight with 59.9 g (327.48 mmol) of N-bromosuccinimide and 145 mg of benzoyl peroxide in 945 ml of carbon tetrachloride. The reaction mixture is filtered through a glass-fiber filter, and after the solvent is spun off, the residue (72.85 g>100%) is incorporated in crude form into the next stage.
Reaction SMILES: [CH2:1]([OH:10])[C@H:2]([CH2:4][CH2:5][C@@H:6]([CH2:8][OH:9])[OH:7])O>S(=O)(=O)(O)O>[OH:10][CH2:1][C@H:2]1[CH2:4][CH2:5][C@@H:6]([CH2:8][OH:9])[O:7]1
Reactant: OC[C@@H](O)CC[C@H](O)CO
Agent: O=S(=O)(O)O
Product: OC[C@@H]1CC[C@H](CO)O1

Procedure:
In a similar fashion, 3,4-dideoxy-threo-hexitol was dehydrated in the presence of sulfuric acid catalyst to give cis-2,5-bis(hydroxymethyl)tetrahydrofuran; di-p-toluenesulfonate, m.p. 128°-129° C., reported m.p. 128°-130° C. (Cope and Baxter, J. Am. Chem. Soc., 77, 393-396 (1955)).
Reaction SMILES: O[CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[N:39]=[C:38]([SH:44])[N:37]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([O:35][CH3:34])[N:37]=[C:38]([S:44][CH:2]([C:7]([O:20][CH3:21])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])[N:39]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
7.16 g (25 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine were added, and 3.2 g (28 mmol) of methanesulfonyl chloride were added dropwise while stirring. The mixture was stirred at room temperature for 2 h, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of DMF. After stirring at room temperature for 2 h and at 60° C. for a further 2 h, the mixture was poured into 1 liter of ice-water, and the resulting precipitate was filtered off with suction. After drying, 3.19 g (29%) of a white powder remained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: CC(C)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(C(C)C)CC3)c2n1
Yield: 636.1 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-isopropylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.040 mL (0.046 mMol) propionyl chloride, 0.092 gm (75%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:5]2[C:6]3[C:11]([CH2:12][N:4]2[N:3]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([NH:1][C:2]1[N:13]=[C:5]2[C:6]3[C:11]([CH2:12][N:4]2[N:3]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2n(n1)Cc1ccccc1-2
Solvent: c1ccccc1
Product: CC(=O)Nc1nc2n(n1)Cc1ccccc1-2

Procedure:
2-Amino-5H-s-triazolo[5,1-a]isoindole (12.08 g) and acetic anhydride (8 ml) are boiled for one hour in 150 ml of benzene. After cooling, the solid precipitate is recovered on filter and then is crystallized from ethyl acetate. Yield 14.35 g (97%). M.p. 258-9°C.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11]Br.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(Cl)Cl>[C:13]([O:16][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Br:1])(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(CBr)c1Br
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)OCc1cccc([N+](=O)[O-])c1Br
Yield: 51.1 %

Procedure:
A stirred solution of 2-bromo-1-bromomethyl-3-nitrobenzene (20.2 g, 0.0685 mole), potassium acetate (10.08 g, 0.103 mole), and tetrabutylammonium chloride (1.5 g) in 150 ml of acetonitrile was heated at reflux for six hours. The reaction mixture was cooled, filtered, and extracted with methylene chloride. The extract was evaporated to give a residue which was redissolved in methylene chloride and washed twice with 150 ml portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated to give a dark solid. The solid was purified by column chromatography on silica gel, elution with toluene, to give (2-bromo-3-nitrophenyl)methyl acetate as a yellow solid (9.6 g, mp 60°-63°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:44]=[CH:45][CH:46]=1)[CH:39]([OH:43])[C:40]([OH:42])=[O:41].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[OH:43][CH:39]([C:38]1[CH:44]=[CH:45][CH:46]=[C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]3=[N:13][CH:14]=2)[CH:37]=1)[C:40]([OH:42])=[O:41]
Reactant: O=C(O)C(O)c1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Yield: 70.4 %

Procedure:
To a mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.04 mmol) and 3-bromomandelic acid (288 mg, 1.25 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL) and sodium carbonate (3 mL, 1 N aqueous solution, 3 mmol). The mixture was purged with nitrogen for 1 min. dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (73 mg, 89 μmol) was added and the purging continued for another minute. The flask was sealed and irradiated in a microwave reactor to 120° C. for 20 min. The reaction mixture was partitioned between aqueous saturated sodium chloride and ethyl acetate (15 mL:15 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford hydroxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a yellow solid (370 mg, 67% yield). MS: m/z 506 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:12]1([CH2:18][CH2:19][CH2:20][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2.77 g of 4-hydroxybenzaldehyde were dissolved in 30 ml of DMF, and 0.95 g of 60% NaH were further added to the resultant solution. The solution was then stirred for 1 hour after elevating the temperature of the solution up to room temperature. After cooling the solution with ice, 4.3 g of 3-phenyl-1-bromopropane were fed dropwise thereto and the solution was then further stirred for 1 hour at room temperature and subsequently for a night at 50-60° C. The solution reacted was poured into ice-water, extracted with ethyl acetate, then the organic layer resulted was dried with anhydrous magnesium sulfate. Then, the solvent used was distillated under reduce pressure, and the residue obtained was purified by using silica gel column chromatography, for which a mixture of hexane and ethyl acetate (mixing ratio, 4:1) was used for the developer, thereby affording 4.9 g of 4-(3-phenylpropyloxy)benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][C:32]=4[CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OC(CCCc1ccccc1)c1cnccc1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ccncc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-(4-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.ClC1C=C(OC(C)C)C([N+]([O-])=O)=CC=1C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:10][C:2]=2[Cl:1])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Oc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)Oc1cc(Cl)c(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1cc(Cl)c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-4-isopropoxy-5-nitro-benzoic acid (Intermediate 8, 10 g, 38.5 mmol) in DCM (200 mL) and DMF (1 mL), is slowly added thionyl chloride (9.17 g, 77 mmol) via a syringe. The mixture is stirred for 3 hours, and is then concentrated to dryness. The obtained white solid, 2-chloro-4-isopropoxy-5-nitro-benzoyl chloride, is dried under vacuum. To a mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.44 g, 7.2 mmol) and triethylamine (3 mL, 21.6 mmol) in DCM (100 mL), is slowly added 2-chloro-4-isopropoxy-5-nitro-benzoyl chloride (2 g, 7.2 mmol) dissolved in DCM (10 mL) via syringe. The mixture is stirred at room temperature for 3 hours, and then is concentrated. The obtained solid is dissolved in ethyl acetate and is washed with water and brine respectively. After evaporation of the solvent, the title compound is obtained as light yellow solid, and is directly used for the next step without further purification.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:58]=CC(N)=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:58][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(N5CC6CCC(C5)O6)c5cnn(C)c5n4)cc3)cc2)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(4-methylpiperazino)aniline as the aniline component. (13%, MS=554.3 (M+H))