Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH2:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)o1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Nc1ccc(I)cc1C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
a magnetically stirred solution of 5 grams of 5-iodoisatoic anhydride (0.0173 mol), 5.85 grams of β-alanine benzyl ester tosylate (0.0173 mol), 35 mL pyridine, and 0.5 of dimethylaminopyridine (0.0041 mol) was heated to 80° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 100 mL ethyl acetate and washed 2×50 mL of 10% cupric sulfate, 1×50 mL sat. sodium bicarbonate, 1×50 mL brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was further purified by column chromatography, using silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.65, υν positive) to yield 1.85 grams (25%) of N-(2-amino-5-iodobenzoyl)-β-alanine benzyl ester. 1H NMR (CDCl3, δTMS) 7.54 (1H, d, 4JHH =2 Hz, Ar--H, o-CON), 7.42 (1H, dd, 3JHH =9 Hz, 4JHH =2 Hz, Ar--H p-CON), 7.38-7.32 (5H, s, ArH Ph), 6.65 (1H, bt, 3JHH =6 Hz, CONH), 6.46 (1H, d, 3JHH =9 Hz, Ar--H m-CON), 5.16 (2H, s, OCH2), 3.68 (2H, q, 3JHH 6 Hz, NCH2), 2.69 (2H, t, 3JHH =6 Hz, CH2CO2). 13C NMR (CDCl3, δTMS) 172.4, 167.8, 148.6, 140.6, 135.6, 135.5, 128.7, 128.4, 128.3, 119.3, 118.1, 76.3, 66.7, 35.2, 34.0.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:20]1([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:29][CH2:22][CH2:21]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.077 g, 0.21 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.200 mL, 0.4 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.81 (m, 6 H) 3.85 (m, 1 H) 6.84 (s, 1 H) 7.49 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.91 Hz, 1 H) 7.62 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=8.09 Hz, 1 H) 8.33 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 415 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][OH:10].C[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Clc1ncccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-bromo-2-chloropyridine (4.76 g) in DMF (30 mL) was added 28% sodium methoxide methanol solution (5.73 g) at room temperature, and the mixture was stirred at 80° C. for 30 min. Water was added at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (4.43 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: NC(CO)c1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol (Chen, L.; et al., US 20060004045) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 68%): mp 94-97° C.; 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.11 (d, J=6.8 Hz, 2H), 8.01 (d, J=6.9 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.3 Hz, 3H), 7.32-7.38 (m, 3H), 5.59 (s, 1H), 3.84-3.87 (m, 2H) (NH, OH not observed); ESIMS m/z 534 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:16]([O-])=O)[C:3]=1[O:19][CH3:20].[H][H]>[Pd].C1COCC1.CN(C=O)C>[NH2:16][C:4]1[C:3]([O:19][CH3:20])=[CH:2][C:7]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=1
Reactant: COc1c([N+](=O)[O-])cc2oc(C(=O)N(C)C)cc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2cc(C(=O)N(C)C)oc2cc1N
Reaction time: 18 h

Procedure:
4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide (500 mg, 1.68 mmol), TEA (184 mg, 1.83 mmol) and 10% palladium on charcoal (90 mg) were stirred at room temperature in THF-DMF (2:1) (30 mL) under an atmosphere of hydrogen for 18 h. The reaction was recharged with hydrogen then allowed to stir for an additional 18 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford a brown solid (400 mg, quant.), which was taken through to the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C)C=O>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)=[O:14])[CH3:17]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CCBr
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc(Cl)cc(Cl)c1
Yield: 49.2 %

Procedure:
In 20 ml of dimethylformamide was dissolved 5.0 g of 3,5-dichloroaniline. To the solution was added 6.16 g of ethyl 3-bromopropionate, followed by heating under reflux for 6 hours. The reaction mixture was concentrated and the concentrate was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected-to silica gel column chromatography (eluent: chloroform:hexane=1:1) to yield 3.98 g of the titled compound as a white crystal.
Reaction SMILES: CS(O)(=O)=O.OO.[Cl:8][C:9]1[CH:44]=[CH:43][CH:42]=[CH:41][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=2[C:14](C=O)=[C:13]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.S([O-])([O-])=[O:46].[Na+].[Na+]>CO>[Cl:8][C:9]1[CH:44]=[CH:43][CH:42]=[CH:41][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=2[C:14]([OH:46])=[C:13]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:28]1
Reactant: O=S([O-])[O-]
Reactant: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: CS(=O)(=O)O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonic acid (21 μl) and a 30% aqueous hydrogen peroxide solution (54 μl) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (132 mg) in methanol (4 ml), and the resulting mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium sulfite solution was added to the reaction solution, followed by extraction with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (54 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27](O)[CH:28]=[CH2:29]>O>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:20][CH2:29][CH:28]=[CH2:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: C=CCO
Reactant: CC(C(=O)O)c1ccc2c(c1)SCC1CCCCC1C2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCOC(=O)C(C)c1ccc2c(c1)SCC1CCCCC1C2=O
Temperature: 110 °C

Procedure:
To a solution of 2-(6,6a,7,8,9,10,10a,11-octahydro-11-oxodibenzo[b,e]thiepin-3-yl)propionic acid (2.0 g) in allyl alcohol (20 ml) was added concentrated sulfuric acid (1 ml) and the mixture was heated under reflux for one hour in an oil bath maintained at 110° C. The reaction mixture was diluted with water and extracted with toluene. The toluene layers were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel, using toluene as an eluent, to give the title compound (1.2 g) as an oil. IR νmaxfilm cm-1 : 1720, 1670 (C=O). HRMS m/e: 344.1415 (Molecular weight calculated for C20H24O3S: 344.1445).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].C([Li])CCC.[CH2:16]([Mg]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]#[N:10]
Reactant: N#CCc1ccccc1F
Reactant: Br[Mg]Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC(Cc1ccccc1)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 2-(2-fluorophenyl)acetonitrile (2.1 g, 15.5 mol) in tetrahydrofuran (50 ml) and hexane (20 ml) was treated with n-butyl lithium (6.2 ml, 15.5 mol) at −78° C. The mixture was stirred at −78° C. for one hour. A solution of benzyl magnesium bromide (2.02 ml, 17.05 mmol) in hexane (10 ml) was added at −78° C. The mixture was stirred at −78° C. for two hours, then warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and extracted in ether. The combined organic layers were washed with brine, dried with magnesium sulfate then filtered and evaporated. Purification by MPLC with 3 to 5% MeOH:CH2Cl2 afforded 2-(2-fluorophenyl)-3-phenylpropanenitrile, (Intermediate 11), (3.4 g).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:19]([N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCn1c(=O)c(C(=O)OCC)nc2ccccc21

Procedure:
3,4-Dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (5 g), allyl bromide (2.8 g) and anhydrous potassium carbonate (15 g) in butanone (100 ml) were stirred and heated under reflux for 3 hours and cooled. The solid was filtered off and the filtrate was evaporated. The residue was crystallised from cyclohexane to give a yellow solid, which had m.p. 77°-79° (56%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CC(C)=O>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:17][CH2:16]1)#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C#N)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
To a solution of ethyl cyanoacetate (11.8 g) in acetone (83.0 mL), potassium carbonate (43.1 g) and 1,2-dibromoethane (39.2 g) were added and the mixture was refluxed for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and further dried under reduced pressure with heating to give ethyl 1-cyanocyclopropanecarboxylate as a red oil (14.2 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[N:26]1([C:31](N)=[NH:32])C=CC=C1.CCN(C(C)C)C(C)C>C1COCC1>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:31]([NH2:32])=[NH:26])[N:4]=2)=[O:10])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N=C(N)n1cccc1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=N)N)cs2)c(C(=O)C2CCCC2)c1
Temperature: 60 °C
Yield: 87.9 %

Procedure:
To a solution of 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methylphenyl)-urea (90 mg, 0.25 mmol) in THF (10 mL) was added pyrrole-1-carboxamidine (54 mg, 0.50 mmol) and DIEA (90 μL). The reaction mixture was heated 60° C. for 3 h and concentrated. The crude product was purified by flash chromatography [silica, DCM:ethyl acetate (50:50 to 10:90)] to yield 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(4-guanidinomethyl-thiazol-2-yl)-urea (88 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([Cl:11])=[C:10]3[C:2]([Br:1])=[N:3]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.2 %

Procedure:
3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B) (5.0 g, 21.42 mmol), 1-benzyl-4-piperidinol (8.2 g, 42.83 mmol) and triphenylphosphine (11.23 g, 42.83 mmol)were suspended in 250 ml of tetrahydrofuran. The reaction mixture was cooled in an ice-water bath and diethyl azodicarboxylate (6.8 ml, 42.83 mmol) was added dropwise. 10 minutes later, the reaction mixture was allowed to warm up to room temperature. After stirring for 2 hours, solvent was removed and the residue was taking into ethyl acetate. The organic layer was washed, dried and evaporated. The crude product was passed through Biotage flash column using dichloromethane/ethyl acetate (90:10) as the mobile phase to yield 10.56 g of 1-(1-benzyl-4-piperidinyl)-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine. The product was 61% pure with a HPLC retention time of 12.46 min. (HPLC condition: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min., the column size is 3.9×150 mm, 300 A).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:7][CH:6]=1)(=O)[CH3:2].C([O-])([O-])=[O:25].[K+].[K+].CN(C=O)C>>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][OH:25])=[CH:6][CH:7]=3)[O:14][C:15]=2[CH:21]=1
Reactant: COc1ccc2cc(C#Cc3ccc(OC(C)=O)cc3)oc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CCc1ccc(OCCO)cc1)C2
Reaction time: 2 h
Yield: 117.2 %

Procedure:
To a stirred solution of the product of Step A (0.05 g, 0.19 mmol) and K2CO3 (0.05 g, 0.36 mmol) in anhydrous DMF (5 ml) ethyl-bromo acetate (0.025 ml, 0.22 mmol) was added at room temperature. The mixture was stirred for 2 h and quenched with saturated NH4Cl solution, extracted in EtOAc (100 ml) and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.07 g; 100%), as pale oil. 1H-NMR (CDCl3) 7.10 (d, 2H, J=8.39 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.80 (t, 2H, J=8.36 Hz); 6.35-6.33 (m, 2H); 4.75-4.71 (m, 1H); 4.56 (s, 2H); 4.22 (q, 2H, J=14.36, 7.17 Hz); 3.72 (s, 3H, OMe); 3.2-3.13 (m, 1H); 2.79-2.69 (m, 3H); 2.0-1.87 (m, 2H); 1.26 (t, 3H, J=7.12 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[OH:28][C@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 71 using 5-bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 71.1) and 5-fluoropyridin-3-ylboronic acid to afford a brown solid. UPLC-MS (Condition 3) tR=0.92 min, m/z=479.1 [M+H]+, m/z=477.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=10.88, 4.28 Hz, 2H) 3.25 (dd, J=10.64, 5.01 Hz, 2H) 3.92-4.02 (m, 2H) 4.90 (d, J=3.79 Hz, 2H) 7.35 (d, J=8.44 Hz, 2H) 7.80-7.84 (m, 1H) 7.84-7.90 (m, 2H) 8.08 (d, J=2.32 Hz, 1H) 8.47-8.53 (m, 1H) 8.61 (d, J=2.69 Hz, 1H) 8.77 (d, J=2.32 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22](#[N:25])[CH:23]=[CH2:24]>C1C=CC=CC=1>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22]#[N:25])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC#N
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Solvent: c1ccccc1
Product: N#CCCN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.00 gram (3.62 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine in 20 milliliters of benzene and 0.38 gram (7.24 millimoles) of acrylonitrile were heated at reflux temperature while progress of the reaction was monitored by TLC. After 2.5 hours, the reaction mixture was cooled to room temperature, and the mixture subjected to reduced pressure to vaporize the benzene solvent and excess acrylonitrile and to obtain a solid residue. The solid was recrystallized from acetonitrile/ethyl acetate to obtain a purified 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(2-cyanoethyl)piperidine product which after drying at 100° C. at 1 millimeter mercury pressure for 2 hours and at room temperature for 15 hours, melted at 165°-168° C. The yield of the product was 760 milligrams (64 percent). A second crop was obtained which after recrystallization from acetonitrile was in the form of white needles, m.p. 169°-170° C. The product had elemental analyses as follows:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:13][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of (1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (496 mg, 3.16 mmol) in chloroform (10 mL) at 0° C. was added phosphorus tribromide (854 mg, 0.30 mL, 3.16 mmol) drop wise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo and the residue purified by flash chromatography (silica gel, 40 g, 20% to 40% ethyl acetate in hexanes) to give 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 63%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[F:15])=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2F)cc1
Reaction time: 12 h
Yield: 81.4 %

Procedure:
A reaction vessel was charged with 12 g of 4-hydroxy-2'-fluoro-4'-bromobiphenyl obtained in Example 4(b), 14.2 g of decyl bromide, 15.7 g of potassium carbonate and 100 ml of 2-butanone (MEK), and the mixture was refluxed with stirring for 12 hours (the disappearance of the starting materials were confirmed by TLC). The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with water and dried over Glauber's salt. The solvents were distilled off and the residue was purified by way of column chromatography on silica gel (eluent:hexane) and then recrystallized from hexane to obtain 14.9 g (81.5%) of 4-decyloxy-2'-fluoro-4'-bromobiphenyl.