Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]1[O:17][C@H:16]1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CS(C)=[O:26]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][C@@H:9]([OH:26])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[CH:15]\[C@@H:16]([OH:17])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CS(C)=O
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(=O)O
Product: CCCCC/C=C\C[C@@H](O)/C=C/C=C/C=C\[C@@H](O)CCCC(=O)O
Reaction time: 0.03 h

Procedure:
Immediately before the assay, LTA4 was diluted to a concentration of 10 μM in assay buffer (without DMSO) and added to the reaction mixture to a final concentration of 2 μM to initiate the enzyme reaction. After incubation for 120 sec at room temperature, the reaction was stopped by ading 2 volumes of chilled quenching buffer, containing acetonitril with 1% acetic acid and 225 nM LTB4-d4 (Biomol). The samples were then kept at 4° C. over night to complete protein precipitation and centrifuged for 15 min at 1800 g. LTB4 formed was measured by LC-MS/MS using LTB4-d4 as an internal standard and an external LTB4 standard (Biomol) as reference. Briefly, the analyte was separated from LTB4 isomers formed by spontaneous hydrolysis of LTA4 using isocratic elution (modified protocol from Mueller et al. (1996), J. Biol. Chem. 271, 24345-24348) on a HPLC system (Waters, Milford, Mass.) and analyzed on a tandem quadrupole mass spectrometer (Waters). MRM transitions followed on 2 channels were 335.2>195.3 (LTB4) and 339.2>197.3 (LTB4-d4). Based on the amounts of LTB4 found at each inhibitor concentration, a dose-response curve was fitted to the data and an IC50 value was calculated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>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.C(O)C>[C:17]1([C:2]2[CH:3]=[C:4]([N:8]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cncc(N2CCN3CCC2CC3)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: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cncc(N3CCN4CCC3CC4)c2)cc1

Procedure:
0.87 g (3.1 mmol) of 4-(5-bromo-3-pyridyl)-1,4-diazabicyclo[3.2.2]nonane is introduced into a 50 ml three-necked round-bottomed flask, 0.39 g (3.15 mmol) of phenylboronic acid, 0.11 g (0.095 mmol) of tetrakis(triphenylphosphine)palladium, 3.3 ml of aqueous 2 M sodium carbonate solution, 6.5 ml of benzene and 0.15 ml of ethanol are added and the mixture is refluxed for 16 h.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][CH2:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>>[Cl:12][CH2:13][CH:14]([CH3:18])[C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: Fc1ccccc1
Reactant: CC(CCl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CCl)C(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of 22.7 g. (0.17 mole) of anhydrous aluminum chloride and 9.6 g. (0.10 mole) of fluorobenzene is added 14.1 g. (0.10 mole) of β-chloroisobutyrylchloride over 30 minutes at 20° to 25°C. The mixture is aged for 30 minutes at 20° to 25°C and then quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-chloro-4'-fluoro-2-methylpropiophenone.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])[CH2:6][CH2:5]1)[CH3:3]>CO.[Ni]>[CH3:21][C:11]1[C:12]([O:19][CH3:20])=[C:13]([CH:14]=[CH:15][C:10]=1[N:7]1[CH2:6][CH2:5][N:4]([CH:2]([CH3:3])[CH3:1])[CH2:9][CH2:8]1)[NH2:16]
Reactant: COc1c([N+](=O)[O-])ccc(N2CCN(C(C)C)CC2)c1C
Agent: [Ni]
Solvent: CO
Product: COc1c(N)ccc(N2CCN(C(C)C)CC2)c1C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A mixture of 1-(1-methylethyl)-4-[2-methyl-3-(methyloxy)-4-nitrophenyl]piperazine (5.5 g, 18.7 mmol) and Raney Ni (2 g) in 200 mL of MeOH was stirred under an atmosphere of H2 overnight. The mixture was filtered and taken to a residue under reduced pressure to afford 3-methyl-4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline as a white solid (4.50 g, 91% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (d, J=6.4 Hz, 6H), 2.24 (s, 3H), 2.73-2.67 (m, 5H), 2.89 (m, 4H), 3.63 (s, 2H), 3.73 (s, 3H), 6.58 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
516 mg (purity 91%, 1.8 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2 eq. of tert-butyl bromoacetate were reacted according to General Method 4B at 100° C. Yield: 464 mg (68% of theory)
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)(O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])(=O)=O>>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][N:5]1[CH2:6][CH2:7][N:2]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:3][CH2:4]1)([O-:31])=[O:30]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2[N+](=O)[O-])cc1
Agent: Cl
Product: O=[N+]([O-])c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 75 %

Procedure:
3-{4-[2-(2-Nitro-phenyl)-ethyl]-piperazin-1-yl}-1,2-benzisothiazole was prepared according to the general method as outlined in Preparation 2 starting with 3-piperazin-1-yl-benzoisothiazole hydrochloride (13.37 g, 52.4 mmol) and 2-nitrophenethyl tosylate (15.3 g, 47.7 mmol). The product was isolated via column chromatography to afford 13.08 g of a viscous, brown liquid. Yield 75%; MS (APCI): 369 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2cccs2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-5-(2-thienyl)-2,4-pentadienoic acid (1.76 g) and 4-nitrophenol (1 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (1.24 g). The mixture was stirred at room temperature for 18 hours then, after the usual work up, the ester was crystallized from 2-propanol to yield 1.45 g of (2E,4Z)-5-(4-methoxyphenyl)-5-(2-thienyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 113°-115° C. A sample was recrystallized from 2-propanol to give the analytical specimen, mp 114.5°-115.5° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19].[F:24][C:25]([F:42])([F:41])[C:26](=[O:40])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([CH3:30])[CH3:29]>C1COCC1>[F:42][C:25]([F:24])([F:41])[C:26]([CH2:13][C:14]1[O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]=1[CH3:19])([OH:40])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([CH3:30])[CH3:29]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1oc2ccccc2c1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1oc2ccccc2c1C)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution of diisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. The reaction mixture was cooled to −78° C. and stirred for 15 minutes. A solution of 2,3-dimethylbenzofuran (48 mg, 0.4 mmol) in 2 mL anhydrous THF was added dropwise to this mixture. After the addition, the reaction mixture was stirred for 15 to 30 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) (Example 1) was added as a solution in anhydrous THF (2 mL) in one portion, the cold bath was removed, and the reaction was stirred at room temperature for 12 hours. THF was evaporated under reduced pressure. Water (2 mL) was added to the residue and the mixture was extracted with three 5 mL portions of EtOAc. The extract was dried over magnesium sulfate. After evaporation, the residue was chromatographed on a silica gel column to provide 80 mg of the title compound as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=O>O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 21 %

Procedure:
4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (59 mg, 21%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-4′-chloroacetophenone (available from Alfa Aesar) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.12 (br s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.09-8.16 (m, 3H), 7.41-7.79 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22]>>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([NH:22][CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)=[N:11][CH:2]=[N:3]2)=[CH:8][CH:7]=1
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: NCCc1ccccn1
Product: Clc1ccc2c(NCCc3ccccn3)ncnc2c1

Procedure:
Analogously to example 17, 2,4,7-trichloro-quinazoline is reacted with 2-pyridin-2-yl-ethylamine to give (7-chloro-quinazolin-4-yl)-(2-pyridin-2-yl-ethyl)-amine and is further reacted
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]
Reactant: COC(CBr)OC
Reactant: Cc1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(COc1ccc(C)cc1Br)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 2 L round bottom flask was cooled to 0° C. a solution of 2-bromo-4-methylphenol (25 g, 133.66 mmol) in anhydrous DMF (940 ml). Then NaH (10.7 g 60% in mineral oil, 267.3 mmol) was slowly added in small portions and the reaction was warmed to room temperature (approx. 0.5 h) after which 2-bromo-1,1-dimethoxy ethane (31.6 ml, 267.4 mmol) was added. The reaction was warmed to room temperature for 3 h and then to 100° C. for 4 h. The reaction was cooled, pass through a silica plug, and concentrated. The brown mixture was diluted with EtOAc, passed through a silica plug again to remove brown solids and concentrated to 24.0 g (65%) amber colored oil: 1H NMR (300 MHz, DMSO-d6): δ 2.23 (3H, s), 3.37 (6H, s), 4.00 (2H, d, J=5.2 Hz), 4.68 (1H, t, J=5.2 Hz), 7.03 (1H, d, J=8.4 Hz), 7.12 (1H, dd, J=8.4 Hz, 1.7 Hz), 7.40 (1H, d, J=1.7 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:6])=[N+]=[N-].[H][H]>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN=[N+]=[N-])COCCCCCCCCCCCCCCCCCCCCCC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN)COCCCCCCCCCCCCCCCCCCCCCC
Yield: 64.7 %

Procedure:
1-Azido-2,2-bis(docosyloxymethyl)propane (12.8 g; 16.8 mmol) and palladium hydroxide on carbon (6.0 g) in tetrahydrofuran (100 ml) was stirred under the hydrogen atmosphere at 50° C. for 3 h. The reaction solution was filtered through celite, and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (60 g of gel, chloroform/methanol, 10:1) to obtain the title compound (8 g, 65%) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>C(OCC)(=O)C>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The compound of example 1 (20.3 g, 0.0944 mol) was dissolved in 150 mL methanol and cooled to 0° C. To this reaction mixture, thionyl chloride (28.07 g, 0.236 mol) was added slowly within 15-20 min. The reaction mixture was stirred at room temperature for 2-3 h. After completion of the reaction, MeOH was removed under vacuum. The oily material obtained was dissolved in ethyl acetate and washed with sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain the title compound.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[C:17](#[N:20])[CH:18]=[CH2:19]>O1CCCC1>[C:1]([C:4]1([CH2:19][CH2:18][C:17]#[N:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: C=CC#N
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
Five hundred g. of 9-carbamoylfluorene was slurried in 13 liters of tetrahydrofuran under nitrogen, and the mixture was stirred and heated to 50°. Fifty ml. of Triton B was added, followed by 131 g. of acrylonitrile. The mixture was stirred at 50° for 6 hours, and 65 g. of additional acrylonitrile and 25 ml. of Triton B were added. The mixture was stirred at 50° overnight.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:17]O>O>[Br:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(Br)c1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(OC)cc1Br
Temperature: 79 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
SOCl2 (7.5 mL, 103.0 mmol) is added dropwise to a stirred 0° C. suspension of 2-bromo-4-methoxybenzoic acid (3) (6.5 g, 28.1 mmol) in methanol (12 mL). The mixture is next stirred at 79° C. for 18 h and then cooled to room temperature before removal of methanol and excess SOCl2 at reduced pressure. The residue is diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL and 70 mL). The extract is washed (2 N NaOH and brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (14.3% to 16.7% ethyl acetate/hexane) to give 5.9 g (85%) of 4 as a colorless liquid. IR 2952, 1728, 1597, 1261 cm−1; 1H NMR (CDCl3) δ 3.83 (s, 3H, CH3O), 3.89 (s, 3H, CO2CH3), 6.86 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.18 (d, J=2.0 Hz, 1H, 3-PhH), 7.85 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].I[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2[NH2:26])[N:19]([CH:27]([CH3:29])[CH3:28])[N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:27]([N:19]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:26])=[C:25]2[C:17]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[N:18]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)cc(OC)c1OC
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of 3,4,5-trimethoxyphenylboronic acid (123 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA64 (70 mg, 89% yield). ESI-MS (M+H)+ m/z calcd 344.1, found 344.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:17]2=[N:16][C:15]=3[NH2:26])=[C:5]([CH3:27])[CH:4]=1.C(O)C>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:17]2=[N:16][C:15]=3[NH2:26])=[C:5]([CH3:27])[CH:4]=1
Reactant: COc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step). To a round bottom flask was added 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (1 eq.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 eq.). The content was degassed (vacuum) followed by hydrogen flush (three times). The reaction mixture was stirred vigorously at room temperature overnight, under a hydrogen balloon. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until the filtrate had no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine. 1H NMR (CDCl3): δ 8.53 (d, 1H), 8.29 (d, 1H), 8.01 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.93 (d, 1H), 6.67 (d, 1H), 6.60 (dd, 1H), 5.93 (bs, 2H), 3.70 (s, 3H), 3.05-3.00 (dd, 2H), 2.93-2.88 (dd, 2H), 2.44 (s, 3H), 2.19 (s, 3H). LRMS [M+H]=358.2
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].O1CCCC1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[O:17][CH:16]=[N:15][C:14]=3[Br:23])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(-c3cnco3)cn12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3ocnc3Br)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A clean, dry, 1 liter 4 neck round bottom flask equipped with mechanical stirring, nitrogen, temperature probe, and a dry ice/acetone bath, was charged with the product from step A (45.2 gr 0.198 moles) and N,N-dimethylformamide (271 ml). The pot was cooled below −60° C. and then lithium hexamethyldisilizane, 1 molar in tetrahydrofuran (198 ml 0.198 moles), was added while keeping the temperature below −60° C. After the addition was complete, the pot was further cooled to below −70° C. and stirred for 1 hour. While stirring, a solution of N-bromosuccinimide (35.24 g 0.198 moles) and N,N-dimethylformamide (105 ml), were stirred in a separate 500 ml round bottomed flask under nitrogen. After the one hour stir at −70° C., the solution of N-bromosuccinimide and N,N-dimethylformamide was slowly added to the anion keeping the temperature below −70° C. This temperature was critical to insure proper selectivity. After the addition was complete, the pot was stirred for one hour below −70° C. The batch was warmed to room temperature and quenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml). The extraction was repeated with a second aliquot of methylene chloride (135 ml), and the combined organic layers washed with a second 1N sodium hydroxide (452 ml) wash. The organic layer was washed with saturated brine solution (452 ml), and dried over magnesium sulfate (50 gr). The magnesium sulfate was filtered off, washed with methylene chloride (135 ml) and the filtrate and wash combined for concentration. The methylene chloride was concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C. A thick slurry formed upon cooling. The solids were granulated at 20 to 25° C. for two hours, filtered, washed with isopropyl ether (50 ml), and dried to afford 53.0 gr of light yellow solids, 96.4% purity (HPLC), 87% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCNc1cccc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: NCCCNc1cccc(Cl)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
3-(3-chlorophenylamino)propanenitrile (2 g, 0.011 mol) was dissolved in anhydrous THF (20 mL) and heated to reflux under nitrogen. A solution of BH3.MeS in THF was added drop wise and stirred at reflux overnight. The resulting solution was cooled to room temperature. Methanol was added drop wise to quench the reaction. After evaporation of the solution, the crude product was purified by column chromatography to afford the pure product N1-(3-chlorophenyl)propane-1,3-diamine (1.89 g, yield 95%)