Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[N:11]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:10]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:35]1COCC1>>[OH:3][CH2:4][CH:6]1[CH2:8][CH:7]1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[N:11]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:35])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[N:10]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CC1c1nn(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(S(=O)(=O)n2nc(C3CC3CO)c3cc(C#N)ccc32)cc1
Temperature: -40 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
2-(1-Benzenesulfonyl-5-cyano-1H-indazol-3-yl)-cyclopropanecarboxylic acid ethyl ester (1.12 g, 2.74 mmol) was dissolved in 30 mL anhydrous THF under N2 and cooled to −40° C. LAH (0.83 g, 22 mmol) was added portionwise over a 15 min. period. The reaction was stirred for 5 h at −40° C., then quenched with 50 mL ethyl acetate, followed by 10 mL water. After stirring at room temperature for 30 min, 50 mL saturated tartrate solution was added and stirred for 30 min. The precipitate was removed by filtration and washed with ethyl acetate. The precipitate was washed with more ethyl acetate, and the organic layer was washed with brine and dried over Na2SO4. Flash chromatography on silica gel using ethyl acetate/hexane (25-50%) as the eluent gave 3-(2-hydroxymethyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indazole-5-carbonitrile (580 mg, 58%). 1H NMR (500 MHz, CDCl3) 8.26 (1H, d, J=8.85 Hz), 8.08 (1H, s), 7.83 (2H, d, J=8.24 Hz), 7.74 (1H, dd, J=8.85, 1.22 Hz), 7.27 (2H, d, J=8.24 Hz), 3.78 (1H, dd, J=11.29, 6.10 Hz), 3.61 (1H, dd, 11.29, 6.71 Hz), 2.38 (3H, s), 2.10 (1H, p, J=4.88 Hz), 1.82 (1H, m), 1.39 (1H, dt, J=8.55, 4.88 Hz), 1.11 (1H, dt, J=8.55, 4.88 Hz). MS m/e 366.15 (M−H)−. Anal. calcd. for C19H17N3O3S: C, 62.11; H, 4.66; N, 11.43. Found: C, 62.16; H, 4.76; N, 11.19.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl-].[Na+].[OH:12][S:13](O)(=[O:15])=[O:14].O=S(=O)=O>>[Br:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([S:13]([OH:15])(=[O:14])=[O:12])[N:4]2[N:3]=1
Reactant: Brc1nn2ccnc2s1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)(O)c1cnc2sc(Br)nn12
Temperature: 80 °C

Procedure:
The starting 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (2.0 g; 9.9 mmol) was dissolved in oleum (4.0 mL) and the resulting solution was heated at 80° C. for 8 hours. The reaction was allowed to cool to room temperature and then poured onto crushed ice. One spoon of sodium chloride was added and the resulting precipitate was isolated by vacuum filtration and washed with cold water. It was dried by azeotrope distillation with toluene. The title compound 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole-5-sulfonic acid was isolated as a beige solid, (2.33 g; 83% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-])=O)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.O>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Br)nc2)cn1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc(Br)nc2)cn1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
5-[(6-bromo-3-pyridinyl)oxy]-2-nitropyridine 65 mg, 0.22 mmol) was dissolved in acetic acid (1.5 ml) and water (2 ml) and heated to 50 degrees C. Iron powder (42 mg, 0.75 mmol) was added and the mixture was left for 1 h. Filtration and purification by column chromatography on silica (ethyl acetate/hexane 2:1) gave 57 mg, 97% of desired product.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][C:7]([NH2:13])=[CH:6][C:5]=2[CH2:4]1.CC1(C)[O:28][C:27](=O)[CH:26]=[C:25]([CH3:30])[O:24]1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:3]1[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][C:7]([NH:13][C:27](=[O:28])[CH2:26][C:25](=[O:24])[CH3:30])=[CH:6][C:5]=2[CH2:4]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CN(CCc1ccccc1)C1CCc2ncc(N)cc2C1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cnc2c(c1)CC(N(C)CCc1ccccc1)CC2
Temperature: 120 °C
Yield: 71.1 %

Procedure:
A 10 mL vial, equipped with a magnetic stirrer, was charged with N6-methyl-N6-(2-phenylethyl)-5,6,7,8-tetrahydroquinoline-3,6-diamine (79 mg, 0.281 mmol), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (48 mg, 0.337 mmol), and toluene (3 mL). The vial was sealed and heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0 to 100% acetone in hexanes) to give the title compound (73 mg, 71%). MS [M+H]+=366.2 m/z.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH:17]=[O:18])=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:24])[CH2:10][C:11]([CH3:23])([CH3:22])[O:12]2)(=O)=O.[C:27]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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:27]1([C:7]2[C:16]([CH:17]=[O:18])=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:14]=[C:13]3[C:8]=2[C:9](=[O:24])[CH2:10][C:11]([CH3:23])([CH3:22])[O:12]3)[CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: OB(O)C1=CCCC1
Reactant: CC(C)c1cc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)C(=O)CC(C)(C)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)c1cc2c(c(C3=CCCC3)c1C=O)C(=O)CC(C)(C)O2
Temperature: 25 °C

Procedure:
A solution of 550 mg (1.39 mmol) of 6-formyl-7-isopropyl-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (Example 19A), 202 mg (1.81 mmol) of cyclopent-1-en-1-ylboronic acid, 112 mg (100 μmol) of tetrakis(triphenylphosphine)palladium and 503 mg (2.37 mmol) of potassium phosphate in 8 ml of degassed dioxane and stirred at 100° C. overnight. After cooling to room temperature, ammonium chloride solution is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is then removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].[C:22](Cl)(Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[C:7]([C:16]([F:17])([F:18])[F:19])=[CH:6][C:5]=1[N:20]=[C:22]=[O:23]
Reactant: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1N=C=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 100 mg (0.312 mmol) of 2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester in 2 ml of dry toluene 1.5 ml of a 20% solution of phosgene in toluene are added at 0° C. After warming to room temperature, a stream of phosgene is introduced into the suspension and simultaneously heating is started. At reflux, the stream of phosgene is maintained for two hours, then replaced by a stream of argon for an additional hour. The toluene is distilled off leaving 126 mg (>100%) of 2-isocyanato-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester as a brown solid, sufficiently pure for the next step. 1H-NMR (CDCl3, 360 MHz): 2.75-2.80 (m, 2H); 3.15-3.20 (m, 2H); 4.00 (s, 3H); 7.40 (s, 1H); 7.95 (s, 1H).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>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.[Cu]I.CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][C:10](=[O:23])[N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:3][CH:4]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(I)nc3)c2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(C#C[Si](C)(C)C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
According to Scheme 33 Step 2: A mixture of 1-((6-iodopyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.48 mmol, 200 mg), PdCl2(PPh3)2 (33 μmol, 23 mg), CuI (24 μmol, 4.5 mg), iPr2EtN (0.99 mmol, 1.72 μl), trimethylsilylacetylene (1.43 mmol, 203 μL) and DMF (3 mL, previously deoxygenated) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 3% yielding 5-(4-methoxyphenyl)-1-((6-(2-(trimethylsilyl)ethynyl)pyridin-3-yl)methyl)pyridin-2(1H)-one (174 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.C(O)(=O)C.[Br:25]Br>O>[Br:25][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)naphthalene (9.68 g, 36.6 mmol) and glacial acetic acid (150 mL) was slowly added a solution of bromine (5.85 g, 36.6 mmol) in glacial acefic acid (20 mL). The mixture was stirred for 1 hour and the resulting suspension was poured into water (200 mL) and the solid product was collected by filtration. The solid was triturated first with water and then with ethyl acetate to yield 11.25 g (90%) of the title compound as a white solid: mp 172–174° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.05 (3H, s), 7.04 (2H, d, J=8.56 Hz), 7.30 (1H, d, J=9.01 Hz), 7.67 (2H, d, J=8.65 Hz), 7.81 (1H, dd, J=1.61 Hz, J=8.84 Hz), 7.87(1H, J=9.04 Hz), 7.94 (1H, d, J=1.47 Hz), 8.27 (1H, d, J=8.92 Hz); MS (El) m/z 343 (M)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:9]#[N:10])([C:7]#[N:8])[CH2:3][CH2:2]1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[NH2:8][CH2:7][C:4]1([CH2:9][NH2:10])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1(C#N)CCOCC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC1(CN)CCOCC1
Temperature: -10 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
Tetrahydro-pyran-4,4-dicarbonitrile (1.52 g) was dissolved in dry THF (25 mL) and cooled to −10° C. To this solution, BH3.THF (56 mL of an 1M solution in THF, 5 equiv.) was added dropwise, the mixture was allowed to warm to room temperature, and subsequently stirred at 60° C. for 6 h. The mixture was cooled in an ice bath, and HCl (24.2 mL of a 6M aqueous solution, 13 equiv.) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was neutralized with 2M aqueous NaOH and extracted three times with DCM. The aqueous layer was evaporated to dryness, the residue was stirred with CHCl3, the solids were filtered off and the organic phase was evaporated under reduced pressure to yield 1.0 g (62%) of a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.46 (t, 4H), 2.74 (s, 4H), 3.67 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:26][N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: COC(=O)CCCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (144.6 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(6-methoxycarbonylhexyl)propanamide (50.6 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: C1([O:6][C:7](=[O:48])[C@@H:8]([NH:40][C:41](OC(C)(C)C)=[O:42])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])CCCC1.[OH-:49].[Na+]>C1COCC1>[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:16]2[C:15]3[C:20](=[CH:21][C:12]([O:11][CH2:10][CH2:9][C@H:8]([NH:40][C:41]([C:15]([CH3:20])([CH3:16])[CH3:14])=[O:42])[C:7]([OH:6])=[O:48])=[C:13]([O:38][CH3:39])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:24][CH:25]=1)(=[O:49])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(=O)C(C)(C)C)C(=O)O
Reaction time: 6 h
Yield: 241.4 %

Procedure:
To a solution of (S)-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-2-tert-butoxycarbonylamino-butyric acid cyclopentyl ester (17 mg, 0.02 mmol) in THF (1 ml) was added 2M NaOH (0.026 ml, 0.046 mmol, 2 eq). After 16 hours reaction was incomplete so an additional 2 equivalents of NaOH was added. The reaction was completed after 6 hours and the THF was removed under reduced pressure. The aqueous layer was diluted with 3 ml of water and acidified to pH 6 with 1M HCl. The title compound was extracted into ethyl acetate, dried over magnesium sulphate and isolated as a white solid (13.8 mg, 91% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=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.[Cl-].[Rh].C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1CCOCC1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of Example 4A (4.405 mmol) in 1:1 ethyl acetate/ethanol (50 mL) was treated with Wilkinson's catalyst (815 mg, 0.880 mmol), degassed three times by freeze-thaw cycle, heated to reflux under nitrogen atmosphere for 2 days, and cooled to room temperature. The solution was adsorbed onto silica gel and purified by flash column chromatography with 50% ethyl acetate in hexane to provide the desired product (1.024 g, 78%). 1H NMR (300 MHz, CD3OD) δ 7.40 (2H, d), 7.10 (2H, d), 3.62 (4H, m), 3.57 (2H, t), 3.38 (2H, t), 2.94 (2H, t), 2.58 (2H, t).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1)=[O:4].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]3[CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(C3CC3)ccc2c1
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A flask containing 6-bromo-naphthalene-2-carboxylic acid methyl ester (1.0 g, 3.7 mmol), cyclopropyl boronic acid (421 mg, 4.9 mmol), palladium acetate (42 mg, 0.02 mmol), tricyclohexylphosphine (106 mg, 0.04 mmol) and potassium phosphate (2.802 g, 13.2 mmol) in toluene (15 ml) and water (0.75 ml) was degassed with N2 for 10 minutes. The reaction was heated at 100° C. for 1 hour. After cooling, the reaction mixture was poured into saturated NaHCO3 solution (100 ml) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (3×50 ml), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 10% EtOAc in hexane) gave the title compound (270 mg, 30%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 0.83-0.87 (2H, m), 1.05-1.11 (2H, m), 2.09-2.16 (1H, m), 3.90 (3H, s), 7.33 (1H, dd, J=8.6 Hz, 1.8 Hz), 7.70 (1H, s), 7.89-7.95 (2H, m), 8.02 (1H, d, J=8.6 Hz), 8.56 (1H, s). LC/MS: m/z not observed; retention time=3.93 min
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[H-].[Na+].[CH2:21](I)[CH:22]=[CH2:23].O>C1COCC1>[CH2:23]([O:10][C@H:8]1[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C@H:5]([C:3]([N:2]([CH3:18])[CH3:1])=[O:4])[CH2:9]1)[CH:22]=[CH2:21]
Reactant: C=CCI
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of 9.6 g of tert-butyl (2S,4R)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate in THF (100 ml) was added 937 mg of NaH and the reaction mixture was stirred at 60° C. for one hour. After returning to room temperature, 12.5 g of allyl iodide was added to the reaction solution, and the reaction mixture was refluxed for one hour. To the reaction solution was added water and the resulting mixture was extracted with EtOAc, then was washed with saturated brine. The organic layer was dried over Na2SO4, then the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=18/1 to 9/1; v/v) to obtain 6.70 g of the title compound (light brown oil).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]3)[N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>C(OC(=O)C)(=O)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=[CH:16][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[C:4]3[C:13](=[CH:12][CH:11]=2)[CH:14]=[CH:15][C:2]([CH:1]=[CH:22][C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[N:3]3)[N:6]=1
Reactant: O=Cc1cccs1
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CC(=O)OC(C)=O
Product: C(=Cc1cccs1)c1ccc2ccc3ccc(C=Cc4cccs4)nc3c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2,9-dimethyl-1,10-phenanthroline (neocuproine hydrate) (10 g, 0.048 mole) and 2-thiophene carboxaldehyde (9.4 ml, 0.188 mole) in acetic anhydride (15 ml) was refluxed for 5 h. The solution was allowed to cool to room temperature to give pale yellow solid. The solid was filtered off under suction and the filter cake was washed with tetrahydrofuran. This was transferred into a conical flask, stirred with de-ionised water for 15 minutes and filtered off under suction. The solid was again washed with tetrahydrofuran and petroleum ether (40-60° C.). The product was dried under vacuum at 80° C. for 8 hours. Yield: 5.9 g. The product was sublimed to give a yellow-orange solid exhibiting intense yellow fluorescence. Its absorption and fluorescence spectra in thin film and in solution in THF are shown in FIGS. 1 and 2.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>O1CCOCC1>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)[CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCNCC2)c1C
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: Cc1c(Cc2ccccc2)nnc(C2=CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Temperature: 160 °C
Yield: 44.4 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine (70 mg, 0.175 mmol) in 2 mL dioxane is added 2-chloro-5-(trifluoromethyl)pyridine (64 mg, 0.35 mmol) and TEA (0.122 mL, 0.88 mmol) in a microwave tube. The reaction mixture is heated at 160° C. for 40 min in a microwave reactor. The mixture is concentrated to afford a brown oil and purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (33 mg, 42%).
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[C:3]([F:12])[CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>>[NH2:11][C@H:7]([C:6]1[CH:5]=[CH:4][C:3]([F:12])=[CH:2][CH:1]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: N[C@@H](C(=O)O)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4 g (R)-4-fluorophenylglycine are suspended in 80 ml of methanol. While cooling with the ice bath 3.28 ml of thionyl chloride are slowly added dropwise, so that the temperature is maintained between 15° C. and 20° C. The reaction mixture is stirred for 12 hours at ambient temperature and then evaporated to dryness. 5.1 g of the product are obtained in the form of the hydrochloride. Analytical HPLC-MS (method A): RT=0.8 min.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:27])[C:25]=1[F:26]>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]3[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (45 mg, 51%), MS (ISP) m/z=356.6 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:11]C)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:13]>CO>[C:1]([NH2:13])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C=Cc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A solution of methyl cinnamate (28 mmol) and 7M ammonia in MeOH (30 ml) was sealed in a 100 ml thick-wall round bottom flashed, and heated at 90° C. with stirring for 72 h, resulting in a brown solution. After the solvent was removed by a rotary evaporator, the crude products were purified by flash silica gel chromatography (eluting with 2-10% MeOH in DCM) to afford cinnamamide.