Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20].O>CS(C)=O>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:17]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=2[C:19]#[N:20])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
To a solution of 6.37 g (0.0317 moles) of N,N-dimethyl-4-hydroxybenzenesulfonamide in 150 ml of DMSO was added 1.27 g (0.0317 moles) of NaOH. The mixture was heated to 60° C. and 5.26 g (0.288 moles) of 2-chloro-5-nitrobenzonitrile added and the mixture heated at 75° C. for 21/2 hrs. The reaction mixture was cooled and poured into a solution of 400 ml of 2 N aqueous NaOH and 300 ml of water. The product was collected by filtration, washed well with water and dried to obtain 8.8 g of product (88% yield). Recrystallization from a mixture of ethanol and dimethylformamide afforded purified N,N-dimethyl-4-(2-cyano-4-nitrophenoxy)benzenesulfonamide, mp 221.5°-223° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][P:5]([CH2:13][C:14](O)=[O:15])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].[N:19]1[CH:24]=CC=C[CH:20]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CNC>C(OCC)(=O)C>[CH3:20][N:19]([CH3:24])[C:14](=[O:15])[CH2:13][P:5](=[O:6])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])[O:4][CH2:3][C:2]([F:18])([F:17])[F:1]
Reactant: O=C(O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CNC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Bis-(2,2,2-trifluoroethyl)phosphonoacetic acid (0.07 mol) was dissolved in 100 ml of ethyl acetate. To this solution 5.6 g of pyridine (0.07 mol) were added, followed by 20.4 g (0.093 mol) of Boc anhydride. The mixture was stirred for 15 min and anhydrous dimethylamine (0.07 mol) was added. The mixture was stirred overnight. The mixture was stirred for 1 h at 5° C., and worked-up. Following distillation bis(2,2,2-trifluoroethyl) 2-(dimethylamino)-2-oxoethylphosphonate was obtained in 80% yield.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(N)c1
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)OC(C)(C)C)c1

Procedure:
2-Guanidino-4-methyl-thiazole-5-carboxylic acid is reacted with tert-butyl (3-amino-phenoxy)-acetate in the same manner as in Example 3. Chromatography on silica gel with methylene chloride-ethyl acetate and methylene chloride-alcohol gives 176 mg of tert-butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, m.p. 204° C., MS: 406 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16](=[O:19])([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][O:25][C:26](=[O:43])[CH:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:43])[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH:29]=1)[O:19][P:16]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])([OH:18])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O
Reactant: COC(=O)C(O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(OP(=O)(O)C(NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: -5 °C
Reaction time: 0.42 h
Yield: 90.2 %

Procedure:
Following a procedure reported by Hoffmann, M., Synthesis (1986), 557A, a solution of (R)-1-(benzyloxycarbonyl)amino-2-methylpropylphosphonic acid (691.0 mg, 2.41 mmol) in 8 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this solution was added thionyl chloride (0.21 mL, 2.88 mmol) and stirred at −5° C. for 25 minutes. Racemic 2-hydroxy-2-(3-(t-butoxycarbonylamino)phenyl)ethanoic acid methyl ester (683.4 mg, 2.43 mmol) was added as a solution in 2 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 4 days (total reaction time 87 hrs), the reaction had almost gone to completion (95%). To this reaction mixture 5 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), acidified to pH 2 with concentrated HCl, and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a mixture of product and starting material. Purification via SiO2 gel flash column chromatography (CH2Cl2, then methanol) provided 1.1966 g (90%) of 2-(3-(t-butoxycarbonylamino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester; as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])=[C:5]([CH3:27])[O:4][N:3]=1.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Temperature: 20 °C
Reaction time: 21 h

Procedure:
To a solution of tert-butyl ((1S)-1-(6-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (105 mg, 0.283 mmol) in anhydrous DCM (3.0 mL) was added 4 N HCl in dioxane (0.40 mL, 1.6 mmol). The solution was stirred at 20° C. for 21 hours and then concentrated in vacuo to give an HCl salt of the title compound as a white solid, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C15H18N4O, 271; found 271.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3/[C:14](=[N:1]/[OH:3])/[C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=N[O-]
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A solution of sodium nitrite (3.3 g, 0.048 mol) in water (14.4 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (4.22 g, 0.02 mol) in acetic acid (80 mL) at room temperature. After the addition was completed, the reaction was stirred for 1.5 hours and 100 mL of water was then added. The mixture was stirred for additional 10 minutes, filtered and dried to give 4.18 g of the desired product. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.48-8.51 (m, 2H), 8.32 (d, 1H, J=5.2 Hz), 7.56 (d, 1H, J=5.6 Hz), 7.07 (dd, 1H, J1=8 Hz, J2=4.8 Hz). MS [M+H]=241.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[C:6]([Cl:9])[C:7]=1I.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=O.N12CCN(CC1)CC2>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:6]1[C:7]2[CH:15]=[C:13]([C:12]([OH:17])=[O:16])[NH:1][C:2]=2[C:3](=[O:11])[N:4]([CH3:10])[N:5]=1
Reactant: Cn1nc(Cl)c(I)c(N)c1=O
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cn1nc(Cl)c2cc(C(=O)O)[nH]c2c1=O
Temperature: 105 °C
Yield: 52.3 %

Procedure:
A mixture of Example 74b (0.59 g, 2.1 mmol), pyruvic acid (0.546 g, 6.2 mmol), 1,4-diazabicyclo[2.2.2]octane (0.695 g, 6.2 mmol), and palladium(II)acetate (0.046 g, 10 mol %) in dimethylformamide (8 mL) was degassed and back-filled with nitrogen three times. The reaction mixture was then heated at 105° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was triturated in 30% ethyl acetate in hexanes to afford 0.25 g (53%) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[C:7]12([CH2:17][CH2:18]O)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>>[Br:6][CH2:18][CH2:17][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: Br
Agent: O=S(=O)(O)O
Product: BrCCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
In a 1 l—roundbottom flask equipped with a reflux condenser 164 g concentrated sulphuric acid and 200 g hydrobromic acid (48% in water) were added subsequently under cooling with an ice bath to 126.20 g (0.70 mole) 2-(1-adamantyl)ethanol. The mixture was refluxed for 6 h and after cooling to room temperature given to 400 g of ice. The aqueous phase was extracted with 400 ml pentane. The organic layer was washed with a 2 M NaOH-solution and with water, dried over magnesium sulphate, and the solvent was removed in vacuo. The product was distilled in vacuo to yield 153.2 g (90%) of (1-(2-Bromo-ethyl)-adamantane as a colourless oil. 1H-NMR (400 MHz, CDCl3): δ=3.29 (t, 2H, CH2Br), 1.71 (t, 2H, CCH2CH2Br), 1.56-1.17 (m, 15H, aliphatic) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9](=O)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1.B.[Na].Cl>C(O)C>[O:14]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccco1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1ccccc1NCc1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
In 20 ml of ethanol was dissolved 5.0 g (45.8 millimoles) of 2-aminophenol, and 4.8 g (50.0 millimoles) of furfural was added to the solution and the mixture was stirred for 1 hour at room temperature. Then, 2.3 g (60.8 millimoles) of sodium boron hydride was added to the mixture and the mixture was stirred at room temperature for 2 hours, and 2N hydrochloric acid was added to the mixture and ethanol was removed by distillation under reduced pressure. Then, the residue was neutralized with a 5% aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure, and the residue was purified by the silica gel column chromatography (developing solvent: ethyl acetate/hexane=3/7) to obtain 5.0 g (the yield was 58%) of 2-(2-furyl)methylaminophenol in the form of a brown oil. The oil was dissolved in 200 ml of an aqueous solution of 2.5 g of sodium hydroxide, and 2.5 ml (30 millimoles) of 1,2-chlorobromoethane was added to the solution and the mixture was heated and refluxed for 5 hours. The reaction mixture was extracted, and the extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oil. The oil was purified by the silica gel column chromatography (developing solvent: chloroform/hexane=1/3→1/1) to obtain 0.5 g (the yield was 7.5%) of intended compound No. 11 in the form of a light-brown oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:32])C(=O)C1>>[Cl:32][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1
Product: O=Cc1ccc(-c2nc3ncc(Cl)n3cc2-c2ccccc2)cc1

Procedure:
The compound was synthesized in a manner according to 4-(3-bromo-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde by using NCS instead of NBS.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N-].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH3:13]>>[O:11]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:12][CH3:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: CCCCCCC(=O)C=[N+]=[N-]
Reactant: CCOc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCC(=O)COS(=O)(=O)c1ccc(OCC)cc1
Yield: 59 %

Procedure:
A 1.0 g quantity of 1-diazo-2-octanone is dissolved in 30 ml of dixoane, and 2.0 g of p-ethoxybenzenesulfonic acid is slowly added to the solution at room temperature. The mixture is stirred until no nitrogen is evolved. The reaction mixture is distilled in a vacuum to remove the solvent, and the residue is extracted with 50 ml of ether, washed with water and dried over anhydrous sodium sulfate. The dried product is distilled in a vacuum to remove the solvent and obtain an oily product, which is purified by column chromatography (silica gel, developer solvent chloroform), affording 1.26 g of 2-oxooctyl-p-ethoxybenzene sulfonate (Compound 46), m.p. 38° to 39° C. Yield 59.0%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH2:53])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1>CN(C=O)C>[NH:37]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N:35]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH:53][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)=[O:15])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1-(Pyridin-4-yl)piperidine-4-carboxylic acid (14 mg, 0.068 mmol), HOBt (12 mg, 0.088 mmol), EDC (17 mg, 0.088 mmol) and sodium bicarbonate (5 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuum. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (12 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH:14]=[CH2:15])=[CH:8][C:7]=1[CH3:16])[CH:2]1[O:4][CH2:3]1.C(O)=[O:18].OO>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[C:7]([CH3:16])=[CH:8][C:9]([CH2:13][CH:14]2[O:18][CH2:15]2)=[CH:10][C:11]=1[CH3:12])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCc1cc(C)c(OCC2CO2)c(C)c1
Reactant: O=CO
Agent: OO
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC2CO2)cc(C)c1OCC1CO1
Yield: 85.5 %

Procedure:
A 350 ml sulfurating flask equipped with thermometer, stirrer, cooler and drip funnel is charged with 21.8 g (0.10 mole) of 4-allyl-2,6-dimethylphenyl glycidyl ether, 10.9 g (0.24 mole) of formic acid and 135 ml of chloroform. At room temperature, 23.2 g (0.47 mole) of hydrogen peroxide are then added dropise over 4 hours. The reaction miture is held at this temperature overnight. It is subsequently taken up in chloroform and the resultant solution is washed twice with 3% NaOH solution until neutral, made peroxide-free with sodium sulfite, dried over sodium sulfate and filtered. The filtrate is concentrated, affording 20.03 g (80.50% of theory) of 4-(2,3-epoxypropyl)-2,6-dimethylphenyl glycidyl ether in the form of a low viscous resin; epoxide content 7.7 equivalents/kg (90.11% of theory).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
Step D (1): A mixture of 4-methyl-1H-imidazole (18.0 g, 53.5 mmol), 1-chloro-2-methoxy-4-nitrobenzene (10.0 g, 53.5 mmol), and potassium hydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 110° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 1000 mL of water. The aqueous mixture was extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (330 g silica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 20% yield) as a yellow/orange solid. LC-MS (M+H)+=234.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.97-8.00 (m, 1 H) 7.93-7.97 (m, 2 H) 7.45 (d, J=8.85 Hz, 1 H) 7.02 (s, 1 H) 4.02 (s, 3 H) 2.35 (s, 3 H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:17]3[CH2:18][CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.9 %

Procedure:
To a stirred mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.9 g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (10 g, 50 mmol, 2.2 equiv) and triphenylphosphine (11.8 g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10° C. was added a solution of diisopropyl azodicarboxylate tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 3 g (33%) of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH2:9]([O:10][C:11]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)=[CH:14][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccc(OCc3ccccc3)cc2)c1

Procedure:
Compound 102 (0.23 g, 7.9 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (15 mL/2 mL/15 mL) was treated with 4-benzloxy phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction mixture was treated with 2 N HCl aq and extracted with EtOAc. The EtOAc layer was washed with saturated NaHCO3 aq, brine and dried over MgSO4. After filtration, the residue was chromatographed on silica gel (1:4 EtOAc/hexanes) to yield the desired product as an orange solid. The orange solid thus obtained was triturated with CH2Cl2 to yield the pdt (2.4 g) as a white solid: Mp=186-187° C.; 1H NMR (DMSO-d6) δ 9.90 (br s, 1 H), 9.05 (br s, 1 H), 7.65 (d, 1 H, J=8.5 Hz), 7.51-7.31 (m, 5 H), 7.19 (d, 1 H, J=8.5 Hz), 7.17 (d, 2 H, J=8.6 Hz), 7.02 (d, 2 H, J=8.7 Hz), 6.86 (dd, 1 H, J=8.5 Hz, 2.4 Hz), 6.70 (d, 2 H, J=1.8 Hz), 6.63 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.86 (s, 1 H), 5.14 (s, 2 H); MS 407 (M−H)−.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=C(c1ccc(OCCCCBr)cc1)c1c(-c2ccccc2)oc2ccccc12
Product: CNCCCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-[4-(4-bromobutoxy)benzoyl]-2-phenylbenzofuran with methylamine according to the procedure described in Example 4 gives 3-[4-(4-methylaminobutoxy)benzoyl]-2-phenylbenzofuran.
Reaction SMILES: [N+:1]([C:4](=O)[C:5]1C=C[CH:8]=[CH:7][CH:6]=1)([O-])=O.C1(O)C=CC=CC=1.[C:19]([OH:22])(=O)[CH3:20]>>[N:1]1[O:22][CH:19]=[C:20]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: CC(=O)O
Reactant: O=C(c1ccccc1)[N+](=O)[O-]
Solvent: Oc1ccccc1
Product: c1ccc2nocc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
α-Nitrobenzaldehyde (15.1 g, 0.100 mol) and phenol 9.46 (0.100 mol) were dissolved in 120 mL of glacial acetic acid in a three-necked round bottom flask. The flask was flushed with N2 (g), and the solution was cooled to 0° C. HCl (g) was bubbled through the solution and then through a sodium hydroxide solution to neutralize the acid. The reaction flask was fitted with a rubber stopper and the solution was allowed to warm to ambient temperature and then stirred for 2 h. HCl (g) was removed by bubbling N2 (g) through the solution. The resulting precipitate was filtered and washed with 15 mL of glacial acetic acid to afford 16.2 g (66%) of anthranil. The anthranil was directly reduced to 2-Amino-5-chloro-4'-hydroxybenzophenone (below) without further purification.