Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][N:24]([CH3:35])[C:25](=[O:34])[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][CH2:26][C:25]([N:24]([CH3:35])[CH3:23])=[O:34])[CH2:33][CH2:32]1)=[O:6]
Reactant: CN(C)C(=O)COC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), N,N-dimethyl-2-(piperidin-4-yloxy)acetamide (82) (0.125 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a cream solid (0.191 g, 61.1% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.98-1.55 (4H, m), 2.96 (3H, s), 3.03 (3H, s), 3.17-3.06 (1H, m), 3.60-3.43 (2H, m), 3.72-3.67 (1H, m), 4.08-3.99 (1H, m), 4.19 (2H, q), 4.28 (2H, s), 7.01 (1H, t), 7.32-7.26 (2H, m), 7.78-7.70 (3H, m), 8.48-8.46 (1H, m), 10.89 (1H, s); m/z (LC-MS, ESI+), RT=1.55 (M+H 467).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl[CH2:39][C:40]1[NH:44][C:43]2[CH:45]=[C:46]([CH3:50])[C:47]([CH3:49])=[CH:48][C:42]=2[N:41]=1>C(#N)C>[CH3:50][C:46]1[C:47]([CH3:49])=[CH:48][C:42]2[NH:41][C:40]([CH2:39][N:11]([CH:9]3[C:10]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][CH2:8]3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])=[N:44][C:43]=2[CH:45]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: Cc1cc2nc(CCl)[nH]c2cc1C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(CN(CCCCN3C(=O)c4ccccc4C3=O)C3CCCc4cccnc43)[nH]c2cc1C
Temperature: 60 °C
Yield: 28 %

Procedure:
To a stirred solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (154 mg, 0.441 mmol), diisopropylethylamine (0.15 mL, 0.861 mmol) and potassium iodide (15 mg, 0.090 mmol) in acetonitrile (2.5 mL) was added 2-chloromethyl-5,6-dimethyl-1H-benzimidazole (prepared according to the procedures described in Bridger et al. U.S. patent application U.S. Ser. No. 09/535,314) (77 mg, 0.426 mmol) and the mixture heated at 60° C. for 18 hours. The mixture was then concentrated and the residue diluted with CH2Cl2 (30 mL). The solution was washed with saturated aqueous NaHCO3 (1×20 mL) and brine (2×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude brown foam. The foam was purified by flash chromatography (1.75 cm ID, 12 g silica, 50:1:1 CH2Cl2: MeOH: NH4OH) to give pure 2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (60 mg, 28%). 1H NMR (CDCl3) δ 1.34-1.51 (m, 2H), 1.53-1.73 (m, 3H), 1.81-2.06 (m, 2H), 2.12-2.22 (m, 1H), 2.34 (s, 6H), 2.55-2.89 (m, 4H), 3.51 (t, 2H, J=7.3 Hz), 3.93-4.08 (m, 3H), 7.1 (dd, 1H, J=7.5, 4.8 Hz), 7.31-7.39 (m, 3H), 7.63-7.67 (m, 2H), 7.72-7.77 (m, 2H), 8.58 (d, 1H, J=4.0 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][NH:32][CH3:33]>CS(C)=O>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH3:33])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCBr
Reactant: CNC
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)C
Reaction time: 2.5 h

Procedure:
8-(6-Bromohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (129 mg, 0.25 mmol) was added to a solution of dimethylamine (2.0 mL, 2M tetrahydrofuran, 4 mmol) and DMSO (0.5 mL) at room temperature. After 2.5 h, the reaction was concentrated to remove the excess amine and tetrahydrofuran. The resulting solution was purified by reverse-phase HPLC to give 4-(3,5-dichloropyridin-4-ylamino)-8-(6-(dimethylamino)hexyloxy)-7-methoxyquinolin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6, HCl salt): δ 10.32 (s, 1H), 10.27 (br, 1H), 9.14 (s, 1H), 8.78 (s, 2H), 7.97 (d, 1H), 7.12 (d, 1H), 4.90 (s, 1H), 3.99 (t, 2H), 3.92 (s, 3H), 2.99 (m, 2H), 2.70 (d, 6H), 1.77 (m, 2H), 1.65 (m, 2H), 1.43 (m, 2H), 1.33 (m, 2H); MS(ESI): 479.0.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:55]([C:62]1[S:66][C:65]([NH2:67])=[N:64][N:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>ClCCl.CN(C)C=O>[CH2:55]([C:62]1[S:66][C:65]([NH:67][C:19]([C:18]2[CH:17]=[CH:16][C:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]3)=[CH:23][CH:22]=2)=[O:21])=[N:64][N:63]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: Nc1nnc(Cc2ccccc2)s1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1

Procedure:
3 g of trans-4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid (9.42 mmol, 1 eq.) are placed in 35 mL of a mixture of dichloromethane and dimethylformamide in a 250 mL round-bottomed flask under a nitrogen atmosphere, at room temperature. 1.528 g of hydroxybenzotriazole (11.1 mmol, 2 eq.), 2.168 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.1 mmol, 2 eq.), 3.11 mL of diisopropylethylamine (18.84 mmol, 2 eq.) and 2.162 g of 5-benzyl-1,3,4-thiadiazol-2-amine (11.1 mmol, 2 eq.) are successively added with stirring. The reaction mixture is stirred for 4 days at room temperature. The reaction medium is evaporated to dryness and diluted in water. The precipitate obtained is filtered off and washed with water. The solid obtained is dissolved in a minimum amount of dichloromethane and chromatographed on silica gel, eluting with a gradient of ethyl acetate in dichloromethane ranging from 2.5% to 25%. 3.13 g of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl)cyclohexyl}acetate are obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1([F:68])[CH2:23][CH:22]([O:24][C:25]2[C:26]3[C:49]([C:50]4[CH:55]=[CH:54][C:53]([C:56](=[O:59])[NH:57][CH3:58])=[CH:52][CH:51]=4)=[CH:48][N:47](COCC[Si](C)(C)C)[C:27]=3[N:28]=[C:29]([NH:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([NH:38][CH:39]4[CH2:42][O:41][CH2:40]4)=[O:37])=[CH:34][C:33]=3[O:45][CH3:46])[N:30]=2)[CH2:21]1>C1COCC1>[F:68][C:20]1([F:19])[CH2:21][CH:22]([O:24][C:25]2[C:26]3[C:49]([C:50]4[CH:55]=[CH:54][C:53]([C:56](=[O:59])[NH:57][CH3:58])=[CH:52][CH:51]=4)=[CH:48][NH:47][C:27]=3[N:28]=[C:29]([NH:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([NH:38][CH:39]4[CH2:40][O:41][CH2:42]4)=[O:37])=[CH:34][C:33]=3[O:45][CH3:46])[N:30]=2)[CH2:23]1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CC(F)(F)C4)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2c[nH]c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CC(F)(F)C4)c23)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
Tetrabutylammonium fluoride (5 equiv) was added to a stirred solution of 4-((4-(3,3-difluorocyclobutoxy)-5-(4-(methylcarbamoyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(oxetan-3-yl)benzamide (1 equiv) in THF (20 mL). The resulting mixture was capped and stirred at 50° C. for 16 h. The crude product was purified to afford the title compound (53.9% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.99 (s, 1H) 8.97 (d, J=6.62 Hz, 1H) 8.57 (d, 1H) 8.41 (d, J=4.41 Hz, 1H) 7.87 (d, J=10.09 Hz, 2H) 7.81 (d, 2H) 7.60 (d, 1H) 7.57-7.62 (m, 1H) 7.50 (d, J=2.21 Hz, 1H) 5.31-5.43 (m, 1H) 4.99-5.09 (m, 1H) 4.81 (t, J=6.94 Hz, 2H) 4.63 (t, J=6.31 Hz, 2H) 3.99 (s, 3H) 3.25 (br. s., 2H) 2.73-2.90 (m, 5H). MS (ESI) m/z 579.0 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>O.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C@@H:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][C@H:10]2[OH:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)cc1

Procedure:
A mixture of 17.5 g. (0.10 mole) of 1-benzyl-3,4-epoxypyrrolidine, 13.4 g. (0.11 mole) of p-methoxyphenol, and 3 drops of water was heated on a steam bath overnight. The dark residue was dissolved in methylene chloride and the solution was washed with two 50-ml. portions of 5% sodium hydroxide. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 23.7 g. of viscous dark oil. This oil was chromatographed on 480 g. of silica gel 60 and the product was eluted with a 1:1 benzene:ether solution. The appropriate fractions were concentrated to give 10.0 g. of a yellow oil which crystallized upon scratching. The solid was recrystallized from cyclohexane to yield 7.2 g. (24%) tan solid, m.p. 84°-5° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][C:25]([O:24][CH3:23])=[O:34])=[CH:28][CH:29]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(C(=O)OC(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester (Intermediate 44 0.025 g, 0.08 mmol), 4-iodo phenyl acetic acid methyl ester (0.027 g, 0.1 mmol), triethyl amine (2 mL), copper(I)iodide (0.008 g, 0.04 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.024 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 40% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.019 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 37.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.029 g (37%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][N:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(Cl)Cl.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CC1CCCO1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([OH:12])=[N:7][N:6]=[CH:5]3)=[CH:16][CH:15]=1
Reactant: Oc1nncc2cc(Br)ccc12
Reactant: Nc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CC1CCCO1
Product: Oc1nncc2cc(Nc3ccc(F)cc3)ccc12
Temperature: 25 °C

Procedure:
A mixture of 6-bromophthalazin-1-ol (1.00 g, 4.44 mmol), 4-fluorobenzenamine (0.642 g, 5.78 mmol), Pd(dppf)Cl2.CH2Cl2 (0.130 g, 0.178 mmol), and lithium bis(trimethylsilyl)amide (2.23 g, 13.3 mmol) in 2-methyltetrahydrofuran (10 mL) was heated at 95° C. in an oil bath for 24 h in a sealed tube. The mixture was cooled to RT, diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated over silica gel. The residue was purified using column chromatography (0-4% MeOH in CH2Cl2) to yield the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 256.0 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)c1ccc(N)cc1F
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OC)c(F)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and methyl 4-amino-2-fluorobenzoate as a beige powder (63%). M− (ESI): 414.1; M+ (ESI): 416.9. HPLC, Rt: 5.58 min (Purity: 96.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Reactant: CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)CC)cc3)ccnc2n1

Procedure:
The product from Example 6 (100 mg, 0.228 mmol) was reacted with ethane sulfonyl chloride (28 mg, 0.228 mmol), N,N-diisopropylethylamine (88.5 mg, 0.685 mmol), and catalytic DMAP in dichloroethane for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (30 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.34 (t, J=7.17 Hz, 3 H) 1.79-1.87 (m, 2 H) 2.40 (s, 3 H) 2.98 (t, J=7.54 Hz, 2 H) 3.47 (q, J=7.35 Hz, 2 H) 6.34 (d, J=7.35 Hz, 1 H) 7.14-7.19 (m, 2 H) 7.27 (d, 2 H) 7.39 (s, 2 H) 7.46 (d, 1 H) 7.78 (d, J=8.46 Hz, 1 H) 8.39 (d, J=6.99 Hz, 1 H) 8.92 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 494 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].C[O-].[Na+].[C:13]1([C:23](OC)=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.Cl>O.CO>[C:13]1([C:23]2[NH:5][N:6]=[C:7]([NH2:9])[N:8]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc2ccccc12
Reactant: N=C(N)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Nc1n[nH]c(-c2cccc3ccccc23)n1
Temperature: 0 °C
Reaction time: 22 h
Yield: 52.3 %

Procedure:
To a stirred mixture of N-aminoguanidine nitrate (2.74 g, 20 mmol) and anhydrous methanol (25 mL) cooled to 0° C. was added sodium methoxide solution (25% in methanol, 4.57 mL, 20 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min before methyl 1-naphthoate (0.93 g, 5 mmol) was added. The mixture was then stirred at 0° C. for 10 min, RT for 10 min, 70° C. for 22 hr, and 75° C. for 19 hr. The reaction mixture was cooled and diluted with 10 mL of water. Concentration under vacuum gave a slightly cloudy solution which was acidified to pH=3-4 with 3 N aqueous HCl solution. The solid obtained was filtered, washed with water, and triturated with ethanol to give 0.55 g (52% yield) of 5-(naphthalen-1-yl)-1H-1,2,4-triazol-3-amine as a yellow solid. (M+H)+=211.16.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].[O-]CC.[Na+].[Na].[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33]I)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][S:9][CH2:33][CH2:32][CH:29]1[CH2:28][CH2:27][N:26]([C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH2:31][CH2:30]1)[NH2:7])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: O=C(OCc1ccccc1)N1CCC(CCI)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)CSCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
In a nitrogen gas flow, 8.3 g of L-cysteine ethyl ester hydrochloride is added to a sodium ethoxide solution prepared by adding 2 g of metallic sodium to 80 ml of absolute ethanol. After stirring for 1 hours at room temperature, 80 ml of an ethanol solution containing 18.4 g of 2-(1-benzyloxycarbonyl-4-piperidyl)ethyl iodide is added dropwise to this reaction mixture. After stirring for 1 hour at room temperature, the reaction liquid is concentrated under reduced pressure. To the resulting residue, ice-cold water is added. After extracting with ether, the organic layer is washed with water, and dried over magnesium sulfate. Thereafter, the solvent is distilled off under reduced pressure to give 16.3 g of oily S-[2-(1-benzyloxycarbonyl-4-piperidyl)ethyl]-L-cysteine ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:3]=1[CH:4]([OH:23])[CH:5]([C:18](OCC)=[O:19])[C:6](=[O:17])[C:7]12[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl.[NH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1.O.CCOC(C)=O>[C:30]([O:29][C:27](=[O:28])[CH2:26][NH:25][C:18]([C:5]1[C:4](=[O:23])[C:3]2[C:13](=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:6]=1[OH:17])=[O:19])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1C(=O)C2(CCOCC2)c2cccc(Cl)c2C1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2cccc(Cl)c2C1=O
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
A mixture of ethyl 5-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-carboxylate (70 mg, 208 μmol) and tert-butyl 2-aminoacetate hydrochloride (52 mg, 312 μmol) in 1 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (81 mg, 624 μmol). The mixture was warmed to 95° C. and stirred for 2.5 hours, cooled to room temperature, and then diluted with 20 mL H2O and 100 mL EtOAc. The organic layers were separated, washed with 20 mL 1N HCl×2, water 20 mL, saturated NaCl 20 mL, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 51 mg pale yellow solid. MS m/e: (M+H)+ 366.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:21])[CH:19]=[CH2:20]>C(O)C>[CH2:18]([NH:21][C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[N:3][C:1]#[N:2])[CH:19]=[CH2:20]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: C=CCN
Solvent: CCO
Product: C=CCNC(=NC#N)NC1CCCc2ccccc21

Procedure:
A solution of 24.5 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 38 ml of allylamine in 400 ml of ethanol was heated at reflux for 87 hours. The solvent was removed from the reaction mixture by evaporation in vacuo, leaving a pale yellow semisolid which was crystallized from isopropyl acetate to give 11 g of N-allyl-N"-cyano-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 130°-132° C.
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:16]([CH2:24][C:25]([CH3:27])=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O.C(O)C>[N+:2](=[C:24]([C:25](=[O:26])[CH3:27])[C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:23])=[N-:3]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(=O)C(=[N+]=[N-])C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of sodium azide (683 mg, 10.5 mmol), p-toluenesulfonyl chloride (2.0 grams, 10.5 mmol), and 70% aqueous ethanol (30 mL) was stirred at room temperature for 1 hour. 1-Benzoylacetone (1.62 grams, 10.0 mmol) and triethylamine (1.46 mL, 10.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours and then poured into deionized water (200 mL). The mixture was extracted with petroleum ether (2×200 mL). The extracts were combined and then washed with a saturated aqueous sodium chloride solution. The organic solution was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 0.980 grams of 2-diazo1-phenyl-1,3-butanedione as a yellow oil. Decomposition temperature: 128° C. (by DSC).