Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)[N:10]3[CH:32]=[CH:33][N:34]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C([O-])(O)=O.[Na+].C(Cl)[Cl:41]>>[Cl:41][C:32]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:34][CH:33]=1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(-c2cc3ncc(Cl)n3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (Example 96; 0.150 g, 0.305 mmol) was suspended in DCM (5 mL) and saturated aqueous NaHCO3 (2 mL). n-Chlorosuccinimide (0.204 g, 1.53 mmol) was added in one portion and the reaction mixture stirred at ambient temperature overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2-3% (9:1 MeOH:NH4OH)/DCM to provide 2-(3-(4-(3-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (0.027 g, 0.051 mmol, 17% yield). MS (apci) m/z=526.0 (M+H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[B:16]([OH:17])[O:15][CH2:14][C:13]=2[CH:18]=1)(O)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[C:23]([C:21]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:16]([OH:17])[O:15][CH2:14][C:13]=3[CH:18]=2)=[C:6]([CH:22]=1)[O:5][CH2:4][C:1]([N:48]([CH2:49][CH3:50])[CH2:46][CH3:47])=[O:2])#[N:24]
Reactant: CCNCC
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1cc(C#N)ccc1Oc1ccc2c(c1)COB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of 5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D17) (1.00 g, 3.08 mmol), EDCI (1.77 g, 9.24 mmol), HOBT (1.25 g, 9.24 mmol), diethylamine (0.96 mL, 9.24 mmol), and 4-dimethylaminopyridine (75 mg, 0.62 mmol) in DMF (20 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (9:1 chloroform/methanol). The combined fractions were put under reduced pressure to remove solvent and then washed with water and toluene. The solvent was again removed under reduced pressure. Another silica gel chromatography column was used (5:5 acetone:hexane). The desired fractions were combined and the solvent was removed under reduced pressure. The residue was recrystallized using hexanes and diisopropylether. Pure 2-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)-N,N-diethylacetamide (0.662 g, 57%) was obtained.
Reaction SMILES: [CH:1]1([CH:4]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[C:5]#[CH:6])[CH2:3][CH2:2]1>C(N(CC)C1C=CC=CC=1)C>[CH:1]1([CH:4]2[CH:5]=[CH:6][C:9]3=[C:10]([CH:11]=[O:12])[CH:13]=[C:14]([O:18][CH3:19])[C:15]([O:16][CH3:17])=[C:8]3[O:7]2)[CH2:3][CH2:2]1
Reactant: C#CC(Oc1cc(C=O)cc(OC)c1OC)C1CC1
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(C=O)c2c(c1OC)OC(C1CC1)C=C2
Temperature: 200 °C
Reaction time: 1 h

Procedure:
2.4 g of (RS)-3-(1-cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-benzaldehyde were dissolved in 20 ml of N,N-diethyl-aniline, heated to 200° C. under argon and stirred at 200° C. for a further 1 hr. The solvent was distilled off at 90° C./1 mbar and the residue was extracted: 2×100 ml of diethyl ether, 2×100 ml of 1N HCl, 2×100 ml of saturated NaCl. The crude product was purified by two-fold silica gel chromatography with dichloromethane and, respectively, ethyl acetate/hexane 5:1. (RS)-2-Cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde was obtained as a brown oil (HPLC 96%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:19][C:17]1[CH:18]=[C:13]([NH2:12])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:20][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Clc1nc2c(Cl)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Oc2nc3c(Cl)cccc3s2)c(Cl)c1
Temperature: 145 °C
Yield: 33.3 %

Procedure:
To solution of 2,4-dichlorobenzothiazole (255, 2.23 g, 11 mmol) and 4-amino-2,6-dichlorophenol (Aldrich, 1.78 g, 10 mmol) in 10 mL of DMSO was add K2CO3 (Aldrich, 4.14 g, 30 mmol). The mixture was heated at 145° C. for 4 h. After cooled to room temperature, the reaction mixture was diluted with EtOAc (300 mL) and filtered through a pad of silica gel and activated carbon followed by washing with EtOAc (500 mL). The filtrate was concentrated and the residue was purified by chromatography (20%-30% EtOAc/Hexanes) to give 1.15 g (33%) of product. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 6.75 (s, 2H), 5.93 (s, 2H). MS (EI): m/z 345 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(C(C)C)C(C)C)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC[C@H](NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.10 g (0.01 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 1.70 g (0.015 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature for 1 hour in 50 ml of tetrahydrofuran and 2.51 g (0.011 mol) of diethyl L-glutamate hydrochloride and 1.8 ml (0.011 mol) of N-ethyldiisopropylamine are then added thereto. After stirring at room temperature for 2 hours the solution is concentrated, extracted with methylene chloride/water, dried with sodium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with methylene chloride-methanol (97:3) and crystallization from ethyl acetate/hexane gives diethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-glutamate as white crystals with melting point 109°-111°.
Reaction SMILES: [C:1]([CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([OH:3])=O.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl.Cl.[CH3:40][O:41][C:42](=[O:47])[C@H:43]([CH2:45][OH:46])[NH2:44]>CN(C=O)C>[CH3:40][O:41][C:42](=[O:47])[C@H:43]([CH2:45][OH:46])[NH:44][C:1](=[O:3])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(CC(=O)O)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)CC(CC(=O)N[C@@H](CO)C(=O)OC)c1ccccc1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a solution of ethyl (±) 4-carboxy-3-phenylbutanoate (1.00 g, 4.23 mmole) in dry DMF (20 mL) was added HOBt (686 mg, 5.08 mmole), Et3N (1.77 mL, 12.69 mmole), and EDC (974 mg, 5.08 mmole). After 30 min, L-serine methyl ester hydrochloride (790 mg, 5.08 mmole) was added. After 48 hr, the mixture was concentrated under reduced pressure. The residue was taken up in CH2Cl2 (50 mL) and washed sequentially with 20 mL each H2O, saturated NaHCO3, and H2O. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (EtOAc) to give the title compound (961 mg, 67%) as a yellow oil: MS (ES) m/e 338 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH:8]([CH2:13][C:14]([O:16]C)=[O:15])[C:9](OC)=[O:10])(=O)[CH3:6].C[O-].[Na+]>CO>[CH3:6][C:5]1[NH:4][C:2](=[S:3])[NH:1][C:9](=[O:10])[C:8]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: NC(N)=S
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]c(=S)[nH]c(=O)c1CC(=O)O
Yield: 72.9 %

Procedure:
Thiourea (4.00 g; 52.5 mmol) and dimethyl acetylsuccinate (9.41 g; 50 mmol) were added at room temperature to a solution of sodium methoxide (22.87 ml; 100 mmol) in methanol (18 ml) and the mixture is stirred under reflux for 18 h. After cooling, the precipitate was filtered off and added with stirring to a hydrochloric acid solution (12N) at 0° C. The white precipitate was filtered, washed with water and dried under reduced pressure over phosphorus pentoxide to give 7.3 g (73%) of title compound as a white powder.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=3)[CH2:3]1.I[C:45]1[NH:49][C:48]([C@@H:50]2[CH2:54][C@H:53]([CH3:55])[CH2:52][N:51]2[C:56](=[O:66])[C@@H:57]([NH:61][C:62](=[O:65])[O:63][CH3:64])[CH:58]([CH3:60])[CH3:59])=[N:47][CH:46]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.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.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]>[CH3:64][O:63][C:62]([NH:61][C@H:57]([C:56]([N:51]1[CH2:52][C@@H:53]([CH3:55])[CH2:54][C@H:50]1[C:48]1[NH:49][C:45]([C:30]2[CH:31]=[C:32]3[CH2:33][O:34][C:21]4[CH:20]=[C:19]5[C:24]([CH:25]=[CH:26][C:16]6[N:15]=[C:14]([C@@H:4]7[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]7[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[NH:18][C:17]=65)=[CH:23][C:22]=4[C:27]3=[CH:28][CH:29]=2)=[CH:46][N:47]=1)=[O:66])[CH:58]([CH3:60])[CH3:59])=[O:65]
Reactant: C[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(I)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Temperature: 95 °C
Yield: 35.1 %

Procedure:
(2S,4S)-tert-butyl 4-methyl-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydorisochromeno [4′, 3′:6,7] naptho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (558 mg, 0.96 mmol), methyl(S)-1-((2S,4S)-2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (501 mg, 1.15 mmol), Pd(PPh3)4 (111 mg, 0.096 mmol), PdCl2(dppf)2 (70 mg, 0.096 mmol), and K2CO3 (2M in H2O, 1.6 mL, 3.17 mmoL) were combined in DMSO (6 mL) and dioxane (6 mL). The mixture was degassed with bubbling N2 for 10 min then heated to 95° C. for 14 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0%-30% MeOH/EtOAc) to afford tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (257 mg, 35%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:15][C:16]#[N:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[Cl-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:15][C:16]#[N:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2CC#N)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1ccccc1-c1ccc(O)cc1
Reaction time: 0.67 h
Yield: 51.6 %

Procedure:
89 mg of 4′-methoxy-2-biphenylacetonitrile was dissolved in 0.66 ml of methylene chloride, and 0.8 ml of a 1 M solution of boron tribromide in methylene chloride was added thereto under cooling with ice, followed by stirring for 40 minutes. This mixture was returned to room temperature and stirred for an additional 40 minutes. After the reaction mixture was poured into a saturated aqueous solution of sodium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 43 mg of 4′-hydroxy-2-biphenylacetonitrile.
Reaction SMILES: C([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:9][CH3:10])[C:4]([O:6]CC)=[O:5])#N.Cl>C(O)(=O)C>[CH3:26][O:25][C:12]1[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:3]([CH2:9][CH3:10])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2C)c1OC
Agent: Cl
Solvent: CC(=O)O
Product: CCC(C(=O)O)c1cccc(Oc2ccccc2C)c1OC
Yield: 63.1 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]butyrate (4.1 g), conc. hydrochloric acid (20 ml) and acetic acid (40 ml) was refluxed under heating for 48 hours. The reaction mixture was evaporated, and 10% aqueous sodium hydroxide and ethanol were added to the residue. The mixture was refluxed under heating for 30 minutes and then evaporated. Water was added to the residue, washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and evaporated to give oily 2-[2-methoxy-3-(o-tolyloxy)phenyl]butyric acid (2.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 38.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (1.01 g, 2.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.01 g, 4.29 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient followed by crystallization from ether/pet ether gave 0.549 g (38%) of the title compound as a tan solid, mp 165-170° C. 1H NMR (DMSO-d6) δ 1.22-1.32 (m, 2H), 1.46-1.58 (m, 2H), 1.61-1.76 (m, 4H), 1.78 (s, 3H), 2.26 (s, 3H), 2.97 (quintet, 1H), 3.84 (s, 2H), 6.94 (d, 2H), 7.23 (d, 1H), 7.34-7.40 (m, 4H), 7.50 (dd, 1H), 7.53 (d, 1H), 8.00 (d, 1H). IR (KBr) 3400, 2950, 1680, 1480, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. for C32H29BrO7S2: C, 57.40; H, 4.37; N, 0.00. Found: C, 57.47; H, 4.24; N, 0.08.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O.COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][C:18]=3[F:20])[CH:3]=2)[CH:8]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2ccc3cc(Br)ccc3c2)c(F)c1
Temperature: 80 °C
Yield: 17.8 %

Procedure:
A mixture of 2,6-dibromonaphthalene (12.49 g, 43.7 mmol), 2,4-difluorobenzeneboronic acid (3.44 g, 21.8 mmol), sodium carbonate (4.63 g, 45.7 mmol), palladium acetate (245 mg, 1.09 mmol) and tri-o-tolylphosphine (667 mg, 2.19 mmol) in water (15 mL) and ethylene glycol dimethyl ether (90 mL) was degassed and heated to 80° C. overnight. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with isohexane, to give 2-bromo-6-(2,4-difluorophenyl)naphthalene (1.24 g, contains 10% 2,6-dibromonaphthalene). 1H NMR (500 MHz, CDCl3) δ 8.04 (1H, s), 7.93 (1H, s), 7.82 (1H, d, J=8.5 Hz), 7.75 (1H, d, J=8.6 Hz), 7.62 (2H, dd, J=8.4, 31.8 Hz), 7.50 (1H, m), 7.04-6.91 (2H, m).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.C(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:17]([O:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:18]
Reactant: CCOC(=O)c1c(O)ncc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCC)ncc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To the title compound of Step A (583 mg, 2.68 mmol) in THF (13 mL) was added triphenylphosphine (1.06 g, 4.03 mmol), ethanol (0.24 mL, 4.03 mmol) and DIAD (0.79 mL, 4.03 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was evaporated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound of Step B (498 mg, 76%). MS (ESI) mass calcd. for C14H15NO3, 245.1. m/z found 246.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ 8.97 (s, 1H), 7.91-7.82 (m, 2H), 7.65-7.60 (m, 1H), 7.42-7.36 (m, 1H), 4.59-4.48 (m, 4H), 1.48-1.39 (m, 6H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[C:7]1[C:16]([O:18]CC)=O)=[N+]=[N-].C(=O)([O-])[O-].[K+].[K+]>CCO.[Pd]>[O:18]=[C:16]1[NH:1][CH2:4][CH2:5][N:6]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[C:7]12
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCN=[N+]=[N-])c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc2n(c1)CCNC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a solution of diethyl 1-(2-azidoethyl)-1H-pyrrole-2,4-dicarboxylate (10 g, 35.68 mmol) in EtOH (1000 mL) was added 10% Pd/C (3 g). The resulting residue was stirred at rt under a 30 psi H2 atmosphere for 2 h. The palladium catalyst was filtered. To the filtrate was added potassium carbonate (5 g, 36 mmol) and the mixture was refluxed overnight. All solids were removed by filtration, and the filtrate was concentrated. Purification via flash chromatography (DCM: methanol, 50:1 to 20:1) afforded ethyl 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (2.5 g, 41%). 1H NMR (DMSO-d6, 300 MHz) δ7.91 (s, 1 H), 7.64 (s, 1H), 6.90 (s, 1 H), 4.18 (m, 4 H), 3.50 (m, 2 H), 1.25 (t, J=5.4 Hz, 3 H).
Reaction SMILES: [CH3:1]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]2=[O:29]>>[CH3:1][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]2=[O:29]
Reactant: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Temperature: 0 °C
Yield: 92 %

Procedure:
In 100 ml of acetone 4.7 g (20 millimoles) of 6-hydroxy-7-ethoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.5 g (2 ml, 30 millimoles) of methyl iodide are added. The reaction mixture is refluxed for 4 hours, the inorganic salt is filtered off, washed twice with 20 ml of acetone and the half of the solvent is removed. The residue is cooled to 0° C., the precipitated product is filtered off and dried to constant weight. Thus 4.6 g of the desired compound are obtained, yield 92%. Mp.: 120°-122° C.
Reaction SMILES: [OH-].[Cu+2:2].[OH-].[NH2:4][CH2:5][C:6]([OH:8])=[O:7]>C(O)C>[NH2:4][CH2:5][C:6]([O-:8])=[O:7].[Cu+2:2].[NH2:4][CH2:5][C:6]([O-:8])=[O:7]
Reactant: NCC(=O)O
Agent: [Cu+2]
Agent: [OH-]
Solvent: CCO
Product: NCC(=O)[O-]
Reaction time: 5 h

Procedure:
The copper hydroxide precipitate was then placed into a beaker provided with a reflux condenser and 15 grams (0.2 Mole) of glycine was added. 100 ml of ethanol was thereafter added and the mixture stirred and boiled at atmospheric pressure for 5 hours. The reaction mixture was then cooled and filtered yielding 21.2 grams of copper glycinate in the form of a fine blue powder.
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[NH2:9].N1C2C(=CC=CC=2)C=CC=1>ClCCl>[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[N:9]=[S:2]([CH3:3])[CH3:1]
Reactant: CSC
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: ClCl
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Product: CS(C)=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
A solution of 1.1 mL (15 mmol) of dimethyl sulfide in 170 mL of dichloromethane was cooled to -10° C. and 0.90 g (13 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 23.3 g (120 mmol) of 2,4,6-trichloroaniline and then 22 g (170 mmol) of quinoline were added with cooling and stirring. The resulting product was a mixture of the title compound and unreacted 2,4,6-trichloroaniline.