Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][CH:18]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:25])[CH2:19][CH2:20][C:21](O)=[O:22])=[C:11]2[CH:10]=[N:9]1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][CH:18]([CH2:19][CH2:20][C:21]([NH:37][CH3:36])=[O:22])[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:25])=[C:11]2[CH:10]=[N:9]1
Reactant: Cc1ccc(NC(=O)C(CCC(=O)O)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)CCC(Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Reaction time: 0.75 h
Yield: 56.8 %

Procedure:
A solution of 4-{[1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}-5-[(5-methylpyridin-2-yl)amino]-5-oxopentanoic acid (5.0 mg, 0.011 mmol), methylamine (0.021 ml (2M in THF), 0.043 mmol) and TBTU (7.0 mg, 0.021 mmol) in THF (1 mL) was stirred at ambient temperature for 5 hrs. Water (1 mL) was added and the reaction mixture was purified by preparative HPLC: Mobile phase A: 100% ACN, Mobile phase B: 5% ACN+95% 0.1M NH4OAc in water; Gradient: 0% A to 50% A over 45 min; Flow: 25 ml/min; UV: 235 nm, to give the title compound (3.0 mg). 1H NMR (500 MHz, CDCl3) δ 8.88 (br s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.11 (m, 2H), 7.62 (m, 1H), 7.51 (m, 4H), 5.91 (m, 1H), 5.63 (br s, 1H), 2.82 (d, 3H), 2.51 (m, 4H), 2.30 (s, 3H), HRMS: calcd for (M+H+) C23H2335ClN7O3: 480.1551. Found: 480.1503.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([F:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[F:16][C:9]1[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][CH:6]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:14][OH:15]
Reactant: C1CNCCN1
Reactant: OCc1cccc(-c2cnc(Cl)nc2)c1F
Solvent: CN(C)C=O
Product: OCc1cccc(-c2cnc(N3CCNCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
[3-(2-Chloropyrimidin-5-yl)-2-fluorophenyl]methanol (600 mg) was mixed with DMF (12 ml), and piperazine (2.2 g) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by stirring at 0° C. for 1 hour. The produced solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure to obtain {2-fluoro-3-[2-(piperazin-1-yl)pyrimidin-5-yl]phenyl}methanol (697 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[C:25]([CH3:41])=[CH:24][N:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[C:26]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[C:25]([CH3:41])=[CH:24][N:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2[nH]c(=O)oc2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(C)cn3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
688 mg (2.50 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 378 mg (1.25 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one (mixture) were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH:11]1([C:16](=O)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:16]2[CH:17]=[C:18]([NH2:19])[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[N:10]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccccc1NN
Reactant: N#CCC(=O)C1CCCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1nc(C2CCCC2)cc1N
Yield: 62 %

Procedure:
A solution of (2-methylphenyl)hydrazine hydrochloride (2.00 g, 14.6 mmol) and crude 3-cyclopentyl-3-oxopropanenitrile from the previous step (2.32 g, ˜14.6 mmol) in toluene (6 mL) was heated to reflux for 16 h. Removal of the solvent under reduced pressure provided a residue which was purified by silica gel chromatography using hexane/EtOAc (3:1, v/v) as the eluent. Concentration under reduced pressure provided 3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine as a light orange solid (2.19 g, 62%). 1H NMR (400 MHz, CDCl3) δ 1.58-1.82 (m, 6H), 2.00-2.16 (m, 2H), 2.17-2.21 (s, 3H), 2.93-3.11 (m, 1H), 3.42-3.58 (s, 2H), 5.41-5.46 (s, 1H), 7.20-7.28 (m, 2H) 7.29-7.37 (m, 2H); ES-MS m/z 241.9 (MH+); HPLC RT (min) 1.69.
Reaction SMILES: C(OC(N1CC[C@H](C2C=CC=CC=2)[C@H](C(O)=O)C1)=O)(C)(C)C.C(OC(N1CC[C@H](C2C=CC=CC=2)[C@H](C([N:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[CH2:46][CH2:45]2)=O)C1)=O)(C)(C)C>>[Cl:56][C:54]1[CH:53]=[CH:52][C:51]([CH3:57])=[C:50]([N:47]2[CH2:46][CH2:45][NH:44][CH2:49][CH2:48]2)[CH:55]=1
Reactant: Cc1ccc(Cl)cc1N1CCN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccccc2)CC1
Agent: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](C(=O)O)C1
Product: Cc1ccc(Cl)cc1N1CCNCC1

Procedure:
In analogy to example 1, step 1, from (3S,4S)-4-phenyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (CAS Reg. No.: [197900-77-9]) and 1-(5-chloro-2-methylphenyl)-piperazine was prepared (3S,4S)-3-[4-(5-chloro-2-methyl-phenyl)-piperazine-1-carbonyl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester as a white foam, MS: 498.5 ([M+H, 1Cl])+.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C.CCOC(C)=O>[N+:18]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]#[N:15])([O-:20])=[O:19]
Reactant: [S-]c1ccccc1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of sodium thiophenolate (16.29 g, 123.3 mmol) in 150 mL of DMF was heated at 100° C. with 4-chloro-3-nitrobenzonitrile (15.0 g, 82.2 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane giving a yellow solid (4.0 g, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Under a nitrogen stream, 5.0 g (0.032 mol) of 4-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 2-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were placed into a 2-neck round flask 250□ and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was added as a catalyst. After the resulting solution was heated to reflux at 80° C. for 24 hours, the reaction was terminated. The resulting mixture was poured into a beaker containing 200□ of distilled water. After extraction with ether (150□) three times, 10 g of magnesium sulfate was added. The resulting solution was stirred by a rotary stirrer for 30 minutes and then the extraction mixture was filtered. After removing the solvent using a rotary evaporator, the residue was subjected to column chromatography using dichloromethane as a developing solvent and then distilled under reduced pressure to give the 2-(4-chloro-phenyl)pyridine. The yield was 56%.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1)=O.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:3]([C:5]2([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]2)=[O:2])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
To a mixture of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4.2 g) and 4-fluoroaniline (3.3 g) in DCM (40 ml) was added EDC (7.4 g) and HOBt (4 g), the reaction was stirred at RT for 4 hours and washed with 1N HCl, NaHCO3 solution, water, brine and dried over Na2SO4. The solution was evaporated and the residue was mixed with NaOH (3.2 g) and MeOH/H2O (60 ml/6 ml). The mixture was refluxed for 30 minutes then was evaporated. The residue was acidified with 4N HCl and the precipitate was filtered. The filter cake was washed with water followed by cold EtOH to give the product as 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid 2.8 g. This product (1.8 g) was mixed with DCM (30 ml) and two drops of DMF. Oxalyl chloride (1.2 ml) was added into the solution and the reaction was refluxed for one hour. The solvent was removed followed by adding DCM (20 ml) and DIPEA (1.3 ml). To the above solution was added 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropylcarbamate (1.5 g), the reaction was stirred at RT for 4 hours. Saturated NaHCO3 (30 ml) and DCM (80 ml) were added into the reaction, the solution was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give the titled compound 2.1 gram. Mass: (M+1), 739
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([CH2:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C(O)=O>N1C=CC=CC=1>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][CH2:14][C:4]3[CH:3]=[C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:40][CH:39]=4)[NH:6][N:5]=3)=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1nc(CCc2ccc3c(c2)OCO3)cc1N
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3cc(CCc4ccc5c(c4)OCO5)n[nH]3)cc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate (229 mg, 0.69 mmol, 1.0 eq) in pyridine (5 ml) at 5° C. was added 4-(4-methylpiperazin-1-yl)benzoyl chloride (181 mg, 0.76 mmol, 1.1 eq). The reaction mixture was stirred to 60° C. for 24 h. After this time, the mixture was concentrated and redissolved in DCM (10 ml). Trifluoroacetic acid (464 μl, 6.25 mmol, 8.25 eq) was added and the reaction mixture stirred for 2 h at 25° C. The reaction mixture was then concentrated. The crude product was purified by reverse-phase prep. HPLC (basic) using a 30-50% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were combined and evaporated to afford the title compound as a white solid. (12 mg, 4%); 1H NMR (300.132 MHz, DMSO) δ 2.28 (s, 3H), 2.49 (t, 2H), 2.89 (s, 2H), 3.31-3.37 (m, 8H), 6.01 (s, 2H), 6.43 (s, 1H), 6.74 (d, 1H), 6.86 (d, 2H), 7.01 (d, 2H), 7.94 (d, 2H), 10.36 (s, 1H), 12.11 (s, 1H); MS: m/z 434 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: COc1ccc(N)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.2 %

Procedure:
1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (5.15 g, 26 mmol, 1.05 eq) was dissolved in dichloromethane (30 mL). A solution of p-methoxyaniline (3.07 g, 25 mmol, 1 eq) in dichloromethane (20 mL) was added dropwise and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and washed with dichloromethane (5 mL×2). The solid was dissolved in ethyl acetate (50 mL), and the resulted solution was washed with diluted hydrochloric acid (1 N, 10 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1-(4-chloro-3-trifluoromethylphenyl)-3-(4-methoxyphenyl)urea A6 (4.5 g, yield 52%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1COCC1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: CN(C)CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (3.0 g, 11.5 mmol) in THF (22 ml) was added at room temperature triethylamine (1.76 ml, 12.6 mmol), the mixture was cooled (ice-water) and a solution of commercially available N,N-dimethyl-ethylenediamine (3.76 ml, 34.4 mmol) in THF (22 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by column chromatography (dichloromethane/methanol/NH4OH 16:1:0.1) to yield the title compound (3.49 g, 97%) as a light yellow oil. MS (ISN) 310.9 [(M−H)−].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=O.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>CN1CCCC1=O>[I:16][C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[N:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1)[N:24]=[CH:10]2
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cesiumcarbonate (29.86 g, 91.6 mmol) is added to a suspension of 2-fluoro-5-iodobenzaldehyde (11.45 g, 45.8 mmol) and 2-pyridylhydrazine (5 g, 45.8 mmol) in 230 mL N-methylpyrrolidon. The reaction mixture is stirred two hours at room temperature. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for three hours at 150° C. The reaction mixture is allowed to cool down and the dark brown suspension is poured into ice water. After vigorously stirring at room temperature for 15 minutes the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4, the solvent is removed i.vac., and the product purified by chromatography on silica gel. Yield 4.8 g (33%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:12][C:13]([OH:15])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:12][C:13]([NH:32][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCC(CC(=O)NCCc2ccccc2)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
Part A. 4-(cyano)-beta-[3-(cyano)phenyl]benzene pentanoic acid (0.150 gm, 0.49 mmol) was dissolved in dry DMF and phenethyl amine (0.065 gm, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.140 gm, 0.74 mmol) and 4-dimethylaminopyridine (0.150 gm, 1.2 mmol) were added. The resulting solution was stirred at room temperature for 48 hrs., quenched in 1 N HCl and extracted with ethyl acetate. The organic phase was washed with 1 N HCl, water and brine and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica gel eluting ethyl acetate:toluene(30:70, v:v) to give 4-(cyano)-beta-[3-(cyano)phenyl]-N-(2-phenylethyl)benzenepentanamide as an oil 0.100 gm (50%). MS: (M+H)+ 408; 1H NMR (CDCl3): 1.9 (m,1H), 2.35 (dd, 1H), 2.45 (m, 2H), 2.7(m, 3H), 3.25(m, 1H), 3.45 (m, 3H), 7.0 (d, 2H), 7.2 (m, 6H), 7.45 (m, 3H), 7.55 (m, 3H).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:36][C:37]1[N:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:38]=1[C:39]([NH2:41])=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:36][C:37]1[N:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:38]=1[C:39]#[N:41]
Reactant: COc1cnc(Cl)c(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(Cl)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
Into a flame dried flask under N2 was placed triphenylphosphine oxide (12.0 g, 0.04 mol) and CH2Cl2 (50 mL) and the mixture cooled to 0°-4° C. A solution of triflic anhydride (6.75 ml, 0.04 mol) in CH2Cl2 (80 mL) was added dropwise. After the addition, the solution was stirred for 15 min. and 2-chloro-5-methoxynicotinamide (8.0 g, 0.04 mol) was added portionwise over 15 minutes. The mixture was allowed to warm to room temperature with stirring overnight, poured into saturated Na2CO3 solution and extracted with CHCl3 (2X). After concentration, the residue was chromatographed on silica gel and the product eluted with CHCl3 to yield 6.2 g (86%) of 2-chloro-5-methoxynicotinonitrile 1H NMR (CDCl3) δ 3.9 (3H, s), 7.5 (1H, d, J=3) and 8.3 (1H, d, J=3); (nujol) 2250 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([Cl:19])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(-c2cccc(F)c2)nc1
Yield: 99.3 %

Procedure:
6-(3-Fluorophenyl)-3-pyridinecarboxylic acid (82 mg, 0.376 mmol) was stirred in dioxane (4 mL) and thionyl chloride (0.137 mL, 1.88 mmol) added dropwise. The reaction mixture was heated at reflux for 40 min then concentrated in vacuo to give 6-(3-fluorophenyl)-3-pyridinecarbonyl chloride as a white solid (0.088 g) which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM and added drop-wise to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.1 g, 0.313 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature under argon for ˜15 h, then diluted with water and DCM. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography. Elution with EtOAc/petroleum ether yielded the title compound as a yellow oil (0.127 g). δH (CDCl3, 400 MHz) 8.51 (1H, d), 7.75 (1H, dd), 7.67 (2H, m), 7.55 (1H, d), 7.40 (1H, m), 7.24 (2H, d), 7.08 (1H, m), 7.03 (2H, d), 4.15 (1H, br.s), 3.78 (1H, d), 3.53 (3H, s), 3.45 (1H, d), 3.32 (1H, d), 3.06 (1H, td), 2.69 (1H, d), 2.49 (1H, d), 2.09 (1H, dd), 1.98 (1H, m), 1.44 (9H, s), 1.16 (3H, d). MS (ES): MH+ 519.3. Description 61
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>>[CH3:1][N:2]1[C:6]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:20][CH2:10][CH2:11][O:12]3)[CH2:14][CH2:15]2)=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cn1cc([N+](=O)[O-])cn1
Product: Cn1ncc([N+](=O)[O-])c1C1(O)CCC2(CC1)OCCO2
Yield: 83 %

Procedure:
Following the procedure for Intermediate 218 starting from 1-methyl-4-nitro-1H-pyrazole and 1,4-cyclohexanedione monoethylene acetal gave 8-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol as a light beige solid (3.68 g, 83%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 4.45 (s, 1H), 4.12 (s, 3H), 4.04-3.93 (m, 4H), 2.44-2.34 (m, 2H), 2.23-1.95 (m, 4H), 1.75-1.67 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:16]2=[N:17][CH:18]=[C:19]3[CH:23]=[N:22][N:21]([CH3:24])[C:20]3=[C:15]2[CH:14]=1.[H-].[Na+].[Na+].[I-].[P:40]([O:52][CH2:53]Cl)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C=O)C>[P:40]([O:52][CH2:53][N:25]1[C:16]2=[N:17][CH:18]=[C:19]3[CH:23]=[N:22][N:21]([CH3:24])[C:20]3=[C:15]2[CH:14]=[C:13]1[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:41]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1COP(=O)(OC(C)(C)C)OC(C)(C)C)cnn4C)cn2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.1 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.00 g, 3.02 mmol [WO2009/152133, Example #42]) and NaH (60 wt % in mineral oil, 0.200 g, 5.00 mmol) were added to DMF (40 mL) then the mixture was stirred at rt for about 10 min. Then NaI (0.068 g, 0.453 mmol) and di-tert-butyl chloromethyl phosphate (1.60 g, 6.19 mmol, [Journal of Medicinal Chemistry (2008), 51(5), 1111-1114]) were added then the mixture was warmed to about 60° C. for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. The material was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was isolated and the aqueous layer was extracted with EtOAc (2×50 mL) then DCM (2×30 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified using an 80 g silica column and eluting with EtOAc to give di-tert-butyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methylpyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl phosphate (0.486 g, 29%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z 554 (M+H)+.