Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cccc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 51.7% yield (0.017 g, 0.047 mmol).
Reaction SMILES: [Na].[OH:2][C:3]1[C:4](=[O:11])[CH:5]=[C:6]([CH2:9][OH:10])[O:7][CH:8]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[OH:10][CH2:9][C:6]1[O:7][CH:8]=[C:3]([O:2][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:11])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: [Na]
Solvent: CO
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
69 g (3 mmol) of sodium were dissolved in 5 l of methanol. Subsequently 425.3 g (3 mol) of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one was added and stirred at 30° C. until a clear solution was obtained. 595 g (3.5 mol) of benzyl bromide was then added and stirred for 1 hour under reflux. The warm, dark colored solution was poured into 15 l of ice water. The product crystallized immediately. The crystals were collected and washed first with 8 l of water and then twice with 2.5 l of ether. The product was left to stand overnight and finally dried at 50° C. for 16 hours. Yield: 646 g.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:6]([CH2:13][C:14](=[O:16])[O-:15])([CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[OH:7])=[O:5]>O>[C:4]([C:6]([CH2:13][C:14](=[O:15])[O-:16])([CH2:8][N+:9]([CH3:11])([CH3:10])[CH3:12])[OH:7])(=[O:5])[CH:3]=[CH2:2]
Reactant: C[N+](C)(C)CC(O)(CC(=O)[O-])C(=O)CCBr
Solvent: O
Product: C=CC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 4 grams of bromopropionyl carnitine in 40 ml of H2O 100 cc of IR 45 amberlite resin activated in OH form were added. The reaction mixture was kept under stirring for 2 hours, then filtered and lyophilized.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]#N)[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].S(=O)(=O)(O)[OH:31]>C1(C)C=CC=CC=1>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH:28]=[O:31])[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: O=S(=O)(O)O
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C#N)CC2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
24 ml of a 1.2M solution of diisobutylaluminium hydride in toluene were added dropwise over a period of 30 minutes at 0° C. and under an inert gas atmosphere to a solution of 5.5 g of trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanecarbonitrile in 500 ml of toluene. The mixture was stirred at 0° C. for another hour and then at room temperature for 3 hours. The mixture was subsequently poured into 500 ml of 0.5N sulphuric acid and extracted three times with 200 ml of diethyl ether each time. The combined organic phases were washed first with saturated sodium hydrogen carbonate solution and then with water, dried over sodium sulphate and concentrated, thereby obtaining 5.6 g of trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanecarboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:11])=[CH:9][NH:8][C:6]=2[N:7]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[N:7]=1
Reactant: Cc1c[nH]c2nc(Cl)ncc12
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccccn2)c2nc(Cl)ncc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
A mixture of 2-Chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.48 mmol), 2-bromopyridine (113 mg, 0.72 mmol), copper(I) iodide (9.1 mg, 0.48 mmol), K3PO4 (2.02 g, 23.84 mmol), and trans-1,2-diaminocyclohexane (5.44 mg, 0.48 mmol) in 1,4-dioxane (7 mL) is stirred at 90° C. for 1.5 hrs. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (anhydrous Na2SO4) and the solvent is evaporated. The crude product is purified by flash chromatography (gradient elution ethyl acetate:heptanes 0:1 to 1:4) on silicagel to afford 2-Chloro-5-methyl-7-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine as a white solid (55%).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])=[CH:9][N:10]=1)(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:5]2[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:12])=[CH:9][N:10]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(N)c1
Reactant: CC(NC(=O)c1ccccc1)c1cnc(S(C)(=O)=O)nn1
Product: COc1cccc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)c1
Temperature: 50 °C

Procedure:
A mixture of N-{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 73) (100 mg) and m-anisidine (1 mL) was heated at 50° C. overnight. The crude reaction mixture was then purified by chromatography on silica gel eluting with 30% ethyl acetate in petrol to give N-[1-(3-{[3-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide as a yellow solid (35 mg). 1H NMR (CDCl3): δ8.39 (s, 1H), 7.82 (m, 2H), 7.51-7.32 (m, 5H), 7.28-7.13 (m, 3H), 6.68 (m, 1H) 5.47 (m, 1H), 3.84 (s, 3H), 1.70 (d, J=6.9 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].O1CCCC1>>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH:14][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CN
Reactant: Cc1ccc(Cl)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(NCC(C)C)c(C)c1
Temperature: 70 °C
Yield: 96.3 %

Procedure:
A mixture of 1-chloro-2,4-dimethylbenzene (1687 mg, 12 mmol), isobutylamine (1755 mg, 24.00 mmol), and Caddick catalyst (140 mg, 0.238 mmol) was treated with lithium hexamethyl disilizide in tetrahydrofuran (1 M LHMDS in THF, 15 mL, 15.00 mmol) under nitrogen. The reaction mixture was heated to 70° C. for 45 minutes in a septum-sealed vessel. The cooled mixture was concentrated in vacuo and the residue was partitioned between aqueous citric acid (50 mL) and tert butyl methyl ether (TBME) (2×50 mL). The organic phase was treated with dried MgSO4, the solid removed by filtration and the organic phase was concentrated in vacuo to give (2,4-dimethylphenyl)(2-methylpropyl)amine (2.05 g, 11.56 mmol) as an orange oil. LCMS [LCMS1] Rt 1.03 min, m/z (ES+) 178 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>S(Cl)(Cl)=O>[NH:22]1[C:21]([NH:20][C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[N:5]=2)=[O:19])=[N:25][N:24]=[N:23]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 66.2 %

Procedure:
In the same manner as described in Example 13-(1), 4-methyl-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (3.0 g), thionyl chloride (20 ml) and 5-aminotetrazole (1.29 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-nitrophenyl)-2-pyridinecarboxamide (2.5 g). M.P. 284°-285° C. (decomp.) (wetted from 278° C.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:25][C:26]5[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=5)[C:29]#[N:30])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(C#N)c5)o4)cc32)cc1
Yield: 24 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 24%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C@@:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH:22][C:35]4[N:36]=[CH:37][C:32]5[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)[C:33]=5[N:34]=4)=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]2(C1)CN(c1ccc(N)nc1)C(=O)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@]5(CCCN(C(=O)OC(C)(C)C)C5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 64 %

Procedure:
Following general N—C coupling procedure 1, (R)-3-(6-amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester as a white solid (0.175 g, 0.275 mmol) in 64% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H) 1.55-1.68 (m, 2H) 1.68-1.85 (m, 3H) 1.88-2.18 (m, 8H) 2.50-2.68 (m, 2H) 3.13-3.21 (m, 6H) 3.21-3.32 (m, 1H) 3.37-3.58 (m, 1H) 3.61-3.72 (m, 1H) 3.75 (d, J=8.53 Hz, 2H) 3.86 (d, J=8.53 Hz, 2H) 4.72-4.95 (m, J=8.91, 8.91, 8.78, 8.53 Hz, 1H) 6.48 (s, 1H) 8.14 (dd, J=9.29, 2.76 Hz, 1H) 8.31 (br. s., 1H) 8.53 (d, J=9.54 Hz, 1H) 8.76 (s, 1H). MS m/z 605.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[S:7](=[O:11])(=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=[CH:23][CH:24]=1.O1CCOCC1>CO.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH:13]1([CH2:12][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([C:20]4[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:3][C:4]=3[N:8]([CH3:9])[S:7]2(=[O:11])=[O:10])[CH2:15][CH2:14]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reactant: CN1c2cc(Br)ccc2N(CC2CC2)S1(=O)=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccnc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-1-(cyclopropylmethyl)-3-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-4) (0.043 g, 0.14 mmol), palladium bis(tri-tert-butylphosphine) (0.014 g, 0.027 mmol), 3-methyl-2-(tributylstannyl)pyridine (0.078 g, 0.20 mmol) and finally dioxane (1 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 1-(cyclopropylmethyl)-3-methyl-5-(3-methylpyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (3-1) as a tan solid. HRMS (M+H)+: observed=330.1270, calculated=330.1271.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:8]([CH3:18])[N:7]=1)=[O:5])C.CO.O[Li].O.Cl>C1COCC1.O>[OH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:18])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2O)n(C)n1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(=O)O)cc1-c1ccccc1O
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.25 g, 0.00078 mole) in DMF (5 mL) was added K2CO3 (0.225 g, 0.00163 mole) followed by methyl iodide (0.116 g, 0.00081 mole) and at the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then quenched with iced water and the resulting precipitate was isolated by filtration. The solid was recrystallized from ethyl acetate to afford 0.251 g (96%) of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 337.15 (M+1)+, 90.13%. To a stirred solution of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.251 g, 0.00075 mole) in methanol (40 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite and the celite was washed with methanol. The combined filtrate was concentrated under reduced pressure to afford 0.169 g (92%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 247.1 (M+1)+, 99%. To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.169 g, 0.00069 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL), was added LiOH.H2O (0.087 g, 0.00206 mol) at ambient temperature and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and acidified with 10% HCl. The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.13 g (87%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS: 219.07 (M+1)+, 81.5%
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[SH:6][C:5]1[S:1][C:2]([S:7][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=2)=[N:3][N:4]=1
Reactant: Sc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#Cc1nccnc1Sc1nnc(S)s1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 1,3,4-thiadiazole-2,5-dithiol (945 mg, 6.05 mmol), NaH (60% dispersion in mineral oil, 264 mg, 6.60 mmol), and 3-chloropyrazine-2-carbonitrile (840 mg, 6.00 mmol) in DMF and benzene (10 ml, 1/1) by stirring at 50° C. under nitrogen atmosphere for 4 hr.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:3]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CC(C)CN
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(F)cc2Cl)nc1Cl
Product: CC(C)CNc1nc(-c2ccc(F)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
2-chloro-6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonitrile (prepared from 6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-1,2-dihydro-2-oxopyridine-3-carbonitrile using conditions similar to Step C Example 1) was reacted with isobutylamine using the conditions of Step A EXAMPLE 27 to afford the title compound. HPLC/MS: 414.1 (M+1), 415.9 (M+3); Rt=4.68 min.
Reaction SMILES: CC1(C)C2[CH:10]=[C:9]([C:12](=[O:30])[CH:13]=[CH:14][C:15]3[CH:29]=[CH:28][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7]C=2C(C2C=CC(C)=CC=2)=CC1.[CH3:39][C:40]1([CH3:59])[C:48]2[C:43](=CC=C(C(=O)C)C=2)[C:42]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)=[CH:41]1>>[CH3:39][C:40]1([CH3:59])[C:48]2[C:43](=[CH:7][CH:8]=[C:9]([C:12](=[O:30])[CH:13]=[CH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])=[O:20])=[CH:28][CH:29]=3)[CH:10]=2)[C:42]([C:52]2[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=2)=[CH:41]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4)ccc32)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)C=C2c1ccc(C)cc1
Product: Cc1ccc(C2=CC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4)ccc32)cc1
Yield: 25 %

Procedure:
Following a procedure similar to that for the preparation of 2-trimethylsilanyl-ethyl 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-naphthalen-2-yl)-3-oxo-propenyl]-benzoate (Compound 6) while using 1-(3,3-dimethyl-1-p-tolyl-3H-inden-5-yl)-ethanone (Compound 14, 200 mg, 0.72 mmol) as the starting material yielded the title compound (93 mg, 25% yield) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)[O:3]1.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1>CC(O)=O.C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=2)[O:3]1
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (100 mg, 0.43 mmol), tert-butyl 4-aminobenzoate (83 mg, 0.43 mmol), NaHB(OAc)3 (273 g, 1.29 mmol) and AcOH (2 drops) in 30 mL of DCM was stirred at room temperature overnight. The mixture was washed with sat NaHCO3 (30 mL), water (2×30 mL), and brine (30 mL) dried over Na2SO4 concentrated under reduce pressure to give a crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamino)benzoate (130 mg) as a black oil. LC-MS: 410 [M+H]+, tR=1.92 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:13][C:14]([CH3:19])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1cccc([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under argon, 11.7 ml (83.32 mmol) of diisopropylamine were dissolved in 200 ml of THF and cooled to −78° C. 33.3 ml (83.32 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to this solution. The reaction solution was then warmed to −10° C. and stirred at this temperature for 10 min. The reaction solution was then once more cooled to −78° C., and 8.4 ml (72.9 mmol) of methyl 2-methylpropanoate were added slowly. The mixture was then stirred at −78° C. for 30 min. 15 g (69.4 mmol) of 1-(bromomethyl)-3-nitrobenzene, dissolved in 150 ml of THF, were then slowly added dropwise. After the addition had ended, the solution was slowly warmed to room temperature and stirred overnight. After TLC check (mobile phase: toluene/ethyl acetate 10:1), saturated ammonium chloride solution was added and the reaction mixture was taken up in ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase toluene/ethyl acetate 20:1). This gave 12.2 g (51.4 mmol, 74% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(C)C)(C)C.[CH:48]1([C:51]#[CH:52])[CH2:50][CH2:49]1>[Cu]I.C(OCC)(=O)C>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([C:52]#[C:51][CH:48]4[CH2:50][CH2:49]4)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(Nc1nc2c(C#CC3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (5.03 g, 10.06 mmol), copper(I) iodide (0.230 g, 1.207 mmol), Pd(allyl)Cl dimer (0.221 g, 0.603 mmol) and tri(2-furyl)phosphine (0.280 g, 1.207 mmol) were combined in a 10-dram vial that was then flushed with nitrogen and kept under a nitrogen atmosphere. MeCN (101 ml) was then added followed by diisopropylamine (4.30 ml, 30.2 mmol) and cyclopropylacetylene (2.57 ml, 30.2 mmol). The resulting solution was then heated to 45° C. and stirred in the dark for 30 min. Then, the reaction was poured into ethyl acetate (350 mL) and washed with sat NaHCO3, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to afford the title compound as a pale yellow solid. LRMS (ESI) calc'd for (C23H25BrN3O) [M+H]+, 438.1; found 438.0.