Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=1)[N:6]=[CH:7]2.C[O:30][C:31]([C@@H:33]1[CH2:37][C@H:36]([N:38]2[CH:42]=[C:41](I)[CH:40]=[N:39]2)[CH2:35][N:34]1C(OCC1C=CC=CC=1)=O)=[O:32].[F-].[K+].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.O>[NH2:28][C:14]1[N:15]=[CH:16][C:17]([C:41]2[CH:40]=[N:39][N:38]([C@@H:36]3[CH2:35][NH:34][C@H:33]([C:31]([OH:32])=[O:30])[CH2:37]3)[CH:42]=2)=[CH:18][C:13]=1[C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[F:12]
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(I)cn2)CN1C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 60 °C

Procedure:
A mixture of 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg, 0.250 mmol), (2S,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (137.0 mg, 0.300 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), potassium fluoride (43.6 mg, 0.751 mmol) and 4:1 dioxane:water (3 mL) was heated in the microwave reactor to 85° C. for 30 min. The material was concentrated in vacuo, then dry-loaded onto silica gel for column chromatography. The product was eluted with 2→5% MeOH/DCM, and the fractions containing the product were concentrated in vacuo. The material was dissolved in conc. HCl, transferred to a sealed tube and heated at 60° C. for 2 h. The solvent was removed in vacuo to afford the title compound as a brown solid. MS (ES+): m/z=453.09/455.10 (100/37) [MH+]. HPLC: tR=1.94 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH2:5][CH:6]([NH:8][C:9](=O)[CH3:10])[CH3:7].O1CCCC1.[ClH:22].C(O)C>C(OCC)C>[ClH:22].[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH2:5][CH:6]([NH:8][CH2:9][CH3:10])[CH3:7]
Reactant: CC(=O)NC(C)COc1c(C)cccc1C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(C)COc1c(C)cccc1C
Temperature: 25 °C
Yield: 75 %

Procedure:
Borane-dimethylsulfide complex (10-10.2M, 35 ml, 1.2 eq) was added to a refluxing solution of N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide (68 g, 0.289 mol) and tetrahydrofuran (400 ml) under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to reflux for 25 hours. The reaction was then cooled to room temperature and 10% hydrochloric acid/ethanol was added until the mixture was acidic. After concentration of the reaction mixture, ethyl ether was added to induce crystallization. The solids were isolated by filtration and dried to give [2-(2,6-dimethylphenoxy)-1-methylethyl]-ethylamine hydrochloride salt (53.0 g, 75% yield, mp 184.7-185.8° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCCCCl)c1ccccc1C(F)(F)F
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[2-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccccc4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-phenoxybenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6](CC)[CH2:7]C)=[O:5].NC1C=CC(Br)=CC=1C(NC)=O>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CNC(=O)c1cc(Br)ccc1N
Product: CNC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with 2-amino-5-bromo-N-methyl-benzamide (920 mg, 4.0 mmol) to give the title compound as 0.35 g of a white solid (32%, over two steps). 1H NMR (CDCl3+CD3OD, 400 MHz): δ=7.65 (s, 1H), 7.64 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.28 (dd, J=8.4, 2.0 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 4.21 (t, J=6.6 Hz, 2H), 3.53 (t, J=5.6 Hz, 2H), 2.90 (s, 3H), 2.00 (m, 2H). MS (ESI): m/z=275.29 [M+H]+. HPLC: tR=2.50 min (ZQ3: polar—5 min).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:10])=[C:5]([C:8]#[N:9])[S:6][CH:7]=1)=[CH2:2].C1C(=O)N(Br)C(=[O:14])C1.[OH-].[Na+]>C(O)(C)(C)C.O>[CH3:10][C:4]1[C:3]([CH:1]2[CH2:2][O:14]2)=[CH:7][S:6][C:5]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1csc(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C2CO2)csc1C#N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of 4-ethenyl-3-methylthiophene-2-carbonitrile (1.70 g, 11.4 mmol) in 30 mL of t-Bu-OH and 60 mL of water was added NBS (2.40 g, 13.7 mmol) portionwise. The mixture was stirred at 90° C. for 1 hour then cooled down to 10° C. Then a solution of NaOH (0.7 g in 10 mL of water, 17.5 mmol) was added dropwise and stirred for 15 minutes. The reaction mixture was extracted with EtOAc twice and concentrated. The residue was purified by silica column chromatography (petrol ether:EtOAc=20:1) to afford 3-methyl-4-(oxiran-2-yl)thiophene-2-carbonitrile.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][OH:42])=[CH:36][CH:35]=1>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:42][CH2:41][CH2:40][C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: OCCc1ccncc1
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCCc2ccncc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml 2-(4-pyridinyl)ethanol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [CH3:1][CH:2]([O:4]/[N:5]=[C:6](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:7]([OH:9])=O)[CH3:3].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:41][CH:42]1[C:67](=[O:68])[N:44]2[C:45]([C:51]([O:53][CH:54]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])=[C:46]([CH2:49][Cl:50])[CH2:47][S:48][C@H:43]12>ClCCl.C(OCC)(=O)C>[Cl:50][CH2:49][C:46]1[CH2:47][S:48][C@@H:43]2[CH:42]([NH:41][C:7](=[O:9])/[C:6](=[N:5]\[O:4][CH:2]([CH3:3])[CH3:1])/[C:10]3[N:11]=[C:12]([NH:15][C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:13][CH:14]=3)[C:67](=[O:68])[N:44]2[C:45]=1[C:51]([O:53][CH:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
A mixture of (Z)-2-(2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IVc) (707 mg, 1.5 mmoles) and phosphorus pentachloride (344 mg, 1.65 mmoles) in dichloromethane (14 ml) was stirred at room temperature for 1 hour and poured into a solution of Compound V (677 mg, 1.5 mmoles) and BSA (1.1 ml, 4.5 mmoles) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 ml), washed with aqueous sodium bicarbonate (100 ml) and water (3×100 ml), dried over sodium sulfate and evaporated to give 1.4 g (100%) of Compound VIc.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.I[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[O:4][CH2:5][CH2:6][N:1]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:25][C:26]=4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1I
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CNCCO1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CN(c2ccccc2C(=O)OC(C)(C)C)CCO1
Yield: 62.8 %

Procedure:
Using N-(morpholin-2-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (120 mg, 0.341 mmol) and tert-butyl 2-iodobenzoate (104 mg, 0.341 mmol), the same procedure was followed as in Example 58 to give 113 mg (63%) of the desired compound as a pale yellow amorphous product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:3]=1.[CH3:17][PH:18](=[O:20])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][P:18](=[O:20])([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1[N+](=O)[O-]
Reactant: C[PH](C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a stirring solution of 4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mmol) and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1 mL of DMF, was added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), Xantphos (55 mg, 0.10 mmol). The reaction mixture was stirred at 110 degrees C. overnight. The reaction mixture was cooled to room temperature and filtered through celite. The desired product was isolated through prep-HPLC to yield a brownish yellow solid (0.24 g, 55% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([O:6]CC)=[O:5].S(=O)(=O)(O)O.[Cl-].[Na+]>>[F:1][C:2]([F:13])([F:14])[CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([OH:6])=[O:5]
Reactant: CCCCC(C(=O)OCC)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC(C(=O)O)C(F)(F)F
Yield: 86 %

Procedure:
Ethyl 2-trifluoromethylhexanoate (10.05 g.) was mixed with 50 ml. of concentrated sulfuric acid and warmed to 75° C. for 20 hours. After cooling, the acid was poured onto excess ice. The resulting mixture was saturated with sodium chloride, extracted with ether (3 × 100 ml.). The combined ether extracts were dried (MgSO4) and evaporated to give a residual oil which yielded 2-trifluoromethylhexanoic acid (7.50 g.) upon distillation, b.p. 80°-85°/2.8 mmHg.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:32]3[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[O:14][C:13]3[C:15]4[C:20]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[C:17]([N:29]([CH3:31])[CH3:30])[CH:16]=4)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:49](Cl)(=[O:52])[CH2:50][CH3:51]>C(Cl)Cl>[CH3:39][N:38]([CH3:40])[C:35]1[CH:36]=[CH:37][C:32]([C:9]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:41])[CH3:1])=[CH:8][CH:7]=3)[O:14][C:13]3[C:15]4[C:20]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH2:27][O:28][C:49](=[O:52])[CH2:50][CH3:51])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[C:17]([N:29]([CH3:30])[CH3:31])[CH:16]=4)=[CH:33][CH:34]=1
Reactant: CCC(=O)Cl
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)C=Cc3c(C(=O)OCCO)cc4ccc(N(C)C)cc4c3O2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCOC(=O)c1cc2ccc(N(C)C)cc2c2c1C=CC(c1ccc(N(C)C)cc1)(c1ccc(N(C)C)cc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2,2-bis(4-dimethylaminophenyl)-5-(2-hydroxyethoxycarbonyl)-9-dimethylamino-[2H]-naphtho[1,2-b]pyran (Example 9, Step 5) (0.045 g, 0.082 mmol) and triethylamine (0.05 ml) in dry DCM (5 ml) was added propionyl chloride in one portion (0.0075 g, 0.082 mmol) and the mixture stirred at RT for 30 minutes. The solvent was then evaporated in vacuo and the crude residue purified by column chromatography (silica gel, DCM/diethyl ether, 10:1), giving the pure product, 2,2-bis(4-dimethylaminophenyl)-5-(2-propionyloxy-ethoxycarbonyl)-9-dimethylamino-[2H]-naphtho[1,2-b]pyran (0.044 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](O)(=[O:14])[C:11]([CH3:13])=O>CO>[Cl:9][C:3]1[C:2]2=[N:1][C:10]([OH:14])=[C:11]([CH3:13])[N:8]=[C:7]2[CH:6]=[CH:5][N:4]=1
Reactant: CC(=O)C(=O)O
Reactant: Nc1ccnc(Cl)c1N
Solvent: CO
Product: Cc1nc2ccnc(Cl)c2nc1O
Temperature: 50 °C
Yield: 65.7 %

Procedure:
A mixture of 3,4-diamino-2-chloropyridine (2.1 g, 14.63 mmol) (Sigma Aldich) and pyruvic acid (1.22 mL, 17.55 mmol) (Acros, New Jersey) in MeOH (40 mL) in a sealed glass tube was heated at 50° C. for 2 h. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was triturated with ether and the suspension was filtered to give 1.88 g of crude product. MS (ESI, pos. ion) m/z: 196.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1.[C:13]1(C)C=CC=C[C:14]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:13]=[CH2:14])=[CH:7][N:6]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: COC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=Cc1ccc(NC(=O)OC)nc1
Temperature: 85 °C
Yield: 439.1 %

Procedure:
A solution of (5-bromo-pyridin-2-yl)-carbamic acid methyl ester (1.68 g, 7.2 mmol) in acetonitrile (15 ml) and triethylamine (1.84 ml) was treated with palladium acetate (65 mg, 0.29 mmol) and tri-o-tolylphosphine (295 mg, 0.97 mmol). The mixture was placed in a pressure reactor under 130 psig of ethylene pressure and heated at 85° C. for 18 hours. The reaction mixture was cooled, vented and diluted with ethyl acetate and filtered. The ethyl acetate solution was washed sequentially with 1M aqueous citric acid, water, brine and was dried over sodium sulfate and filtered. The filtrate was evaporated. The residue was recrystallized from dichloromethane-hexane to afford 0.759 g (58%) of the title product as colorless crystals. mp 146-148° C. 1H NMR (CDCl3): δ=9.04 (br, 1 H): 8.28 (d, 1 H); 7.97 (d, 1 H); 7.77 (d of d, 1 H); 6.64 (d of d, 1 H); 5.71 (d, 1 H); 5.26 (d, 1 H); 3.81 (s, 3H). MS (Cl): m/z =179 (M+H+).
Reaction SMILES: IC1SC=CC=1.C[O-].[O-]CC.[O-:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[C:20]1[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=1>>[O:12]([C:20]1[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [O-]c1ccccc1
Reactant: O=C(O)c1ccc(O)s1
Agent: CC[O-]
Agent: C[O-]
Agent: Ic1cccs1
Product: O=C(O)c1ccc(Oc2ccccc2)s1

Procedure:
The latter compounds are alternatively prepared by reaction of 2-iodothiophene with methoxide, ethoxide or phenoxide, followed by carbonylation according to Sice [J. Am. Chem. Soc. 75, 3697 (1953)], or by alkylation of 5-hydroxythiophene-2-carboxylic acid by the method of Gronowitz [Ankiv Kemi 12, 239 (1958); Chem. Abstr. 52, 20115].
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:6][O:5][C:4]1[CH:3]=[CH:2][C:1]([C:9](=[O:10])[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[CH:18][CH:19]=2)[C:20]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:29])=[CH:8][CH:7]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of desoxyanisoin (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,2,3-tris(4-methoxyphenyl)propane-1,3-dione.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[OH:10].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]([OH:10])[C:5]1[S:6][CH:7]=[CH:8][C:4]=1[CH:3]=[O:2]
Reactant: COC(OC)c1ccsc1C(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1ccsc1C(O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred slurry of acidic silica gel (prepared from 36 g of silica gel, 120 ml of dichloromethane, and 6.6 ml of 15% aqueous sulfuric acid) was added 3-(dimethoxymethyl)-α-(2-fluorophenyl)-2-thiophenemethanol in dichloromethane (45 ml). The reaction mixture was stirred at room temperature for 1.5 hrs, poured over anhydrous potassium carbonate, and filtered. Concentration of the filtrate gave 2-[(2-fluorophenyl)hydroxymethyl]-3-thiophenecarboxaldehyde.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>O>[O:11]=[C:3]1[NH:4][C:5]2[CH:10]=[C:9]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:8]=[CH:7][C:6]=2[S:1][CH2:2]1
Reactant: O=C1CSc2ccccc2N1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
4H-Benzo[1,4]thiazin-3-one (7.0 g) was added cautiously portionwise to chlorosulfonic acid (15 ml) at 0° C. over 20 minutes and the solution was stirred cold for 1 hour and then heated at 45° C. for 2 hours. It was cooled and poured slowly into iced-water. The product was collected, washed well with water and dried in vacuo to give a white solid (7.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: OB(O)c1ccc(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: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(F)cc2)cn1
Temperature: 77.5 °C
Yield: 69.8 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (1.0 g, 4.99 mmol) in toluene (100 mL) and ethanol (50 mL) was added 4-fluoro phenyl-boronic acid (1.4 g, 9.99 mmol), 2M sodium carbonate (3.7 g, 34.99 mmol, 12 mL water), Pd(PPh3)4 (0.228 g, 0.25 mmol) under argon. The resulting mixture was heated at 75-80° C. for 6 h. The contents were cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with bicarbonate solution (2×100 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate and distilled off to obtain the crude product. The product was purified by flash chromatography (100-200μ; 35% ethyl acetate in hexane) to afford 1-(5-(4-fluorophenyl)pyridin-2-yl)ethanone (0.75 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.86 (m, 2H), 7.36 (t, 2H), 2.65 (s, 3H); LC-MS m/z calculated for [M+H]+ 216.23 found, 216.0.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH3:14][C:15]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])[CH3:16]>O1CCOCC1.O.C(OCC)(=O)C>[C:15]([O:18][C:19]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:20])([CH3:17])([CH3:16])[CH3:14]
Reactant: NCCC(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
Triethylamine (6.2 mL, 45 mmol) was added to a solution of 3-aminopropionic acid (2.67 g, 30.0 mmol) in 50% aqueous dioxane (30 mL). BOC-ON (8.15 g, 33.1 mmol) was added and the reaction stirred for 3 h at room temperature. The reaction solution was diluted with H2O (40 mL) and ethyl acetate (60 mL). The aqueous layer was isolated, washed with ethyl acetate, and acidified with a 5% citric acid solution. The aqueous layer was subsequently extracted with ethyl acetate. The organic fractions were combined and evaporated to yield L2 as a cream solid (3.64 g, 62.8%). 1H NMR (d6-DMSO, 300 MHz): δ 1.35 (s, 9H, CH3), 2.33 (t, 2H, CH2), 3.11 (q, 2H, CH2), 6.67 (t, 1H, NH).