Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)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: C1COCCO1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)NC2(C)C)cc1
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (500 mg, 1.01 mmol) in 1,4-dioxane (20 mL) were added 4-methoxyphenylboronic acid (185 mg, 1.2 mmol), Na2CO3 (256 mg, 3.04 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (117 mg, 0.1 mmol) was added. Stirring was continued at 80° C. for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (30 mg, 7%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.20-8.01 (m, 2 H), 7.87-7.62 (m, 2 H), 7.61-7.51 (m, 2 H), 7.38-7.30 (m, 2 H), 7.16-7.09 (m, 2 H), 6.91 6.80 (m, 4 H), 5.96 (bs, 1 H), 5.39 (s, 2 H), 3.81 (s, 3 H), 1.43 (s, 6 H). MS: M+H: m/z=451.2 and HPLC: 94%, (Condition-I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:35])[NH:21][C:22]3[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[C:25](Br)=[CH:24][C:23]=3[Cl:34])=[CH:16][N:15]=2)[C@H:10]([CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39](=[O:75])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][C@@H:50]([CH3:52])[CH2:49][C@H:48]1[C:53]1[NH:57][C:56]2[C:58]3[C:63]([CH:64]=[CH:65][C:55]=2[N:54]=1)=[CH:62][C:61](B1OC(C)(C)C(C)(C)O1)=[CH:60][CH:59]=3)=[O:46])[CH:42]([CH3:44])[CH3:43].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=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].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:35])[NH:21][C:22]3[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[C:25]([C:61]4[CH:62]=[C:63]5[C:58](=[CH:59][CH:60]=4)[C:56]4[N:57]=[C:53]([C@@H:48]6[CH2:49][C@H:50]([CH3:52])[CH2:51][N:47]6[C:45](=[O:46])[C@@H:41]([NH:40][C:39]([O:38][CH3:37])=[O:75])[CH:42]([CH3:43])[CH3:44])[NH:54][C:55]=4[CH:65]=[CH:64]5)=[CH:24][C:23]=3[Cl:34])=[CH:16][N:15]=2)[C@H:10]([CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)OC(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)ccc32)[nH]1)C(C)C
Temperature: 90 °C
Yield: 57.7 %

Procedure:
To a solution of (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.19 mmol) and ((S)-2-methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (100 mg, 0.19 mmol) dissolved in toluene (1.19 mL) and water (0.43 mL) was added potassium carbonate (128 mg, 0.93 mmol). The reaction mixture was sparged with nitrogen for 15 min and Pd(dppf)Cl2 CH2Cl2 (13.6 mg, 0.017 mmol) was added. The reaction mixture was sparged with nitrogen, heated at 90° C. overnight, cooled to RT, diluted with EtOAc and washed with water and brine to produce a dark colored oil, which was purified by silica gel chromatography (24 g silica, 40% to 100% EtOAc/hexane) to produce the title intermediate (101 mg; 59% yield) as a yellow solid. (m/z): [M+H]+ calcd for C46H52ClF3N8O6 921.36 found 921.3.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:34]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2o1
Yield: 94.6 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), benzofuran-2-carboxylic acid (2.0 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.4 g, 96%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21]CC4C=CC=CC=4)[CH:16]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.B(Br)(Br)Br.CCOCC>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccc(OCc3ccccc3)c1)CC2
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(O)c1)CC2
Yield: 71 %

Procedure:
Prepared from 2-amino-6-(3-(3-benzyloxy-phenyl)allyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine with 2 equivalents of boron tribromide in methylene chloride. Yield: 71% of theory, Melting point: 85°-95° C. (ether); foamy.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[CH:35]=[C:34]([O:36][Si](C(C)(C)C)(C)C)[CH:33]=[CH:32][C:31]=1B(O)O>COCCOC.O.CCOC(C)=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:29][C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)c(Cl)c1
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
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
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3Cl)ccc12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (0.97 g, 2.91 mmol), tetrakis(triphenylphosphine)palladium (0) (0.13 g, 0.116 mmol), 2 M Na2CO3 (13.6 mL) and 2-chloro-4-[((1,1-dimethylethyl)dimethylsilyl)oxy]phenylboronic acid (1 g, 3.49 mmol) in ethylene glycol dimethyl ether (15.5 mL) was heated at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, and transferred to a separatory funnel. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an oil. The crude material was purified by flash chromatography over SiO2 with a Hex:EtOAc (0 to 20% EtOAc) gradient to afford 0.74 g (82%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1 H), 8.75 (d, J=9 Hz, 1 H), 8.22 (d, J=8 Hz, 1 H), 8.13 (d, J=7 Hz, 1 H), 8.01 (s, 1 H), 7.68 (m, 1 H), 7.61 (t, J=8 Hz, 1 H), 7.34 (d, J=9 Hz, 1 H), 6.96 (m, 1H), 6.86 (m, 1 H), 3.93 (s, 3 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>COCCOC>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Solvent: COCCOC
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12

Procedure:
(rac)-6-Chloro-3-[1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Stage 278.1), 240 mg, 0.728 mmol) was introduced in a microwave reactor together with 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (227 mg, 1.092 mmol) and DME (5 mL). The mixture was purged with argon for 5 min. Tetrakis-(triphenylphosphine)-palladium (42.1 mg) and 2 M Na2CO3 (1.31 mL) were added and the mixture was flushed with argon before being sealed. The RM was submitted to microwave irradiation at 150° C. 30 min. Then it was diluted with EtOAc and washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to afford the title compound as a white solid (tR 1.03 min (conditions 2), MH+=376) 1H-NMR in DMSO-d6: 8.29 (s, 1H); 8.05 (d, 1H); 7.93 (s, 1H); 7.67 (s, 1H); 7.58 (d, 1H); 7.53 (d, 1H); 7.46 (d, 1H); 7.23 (d, 1H); 4.92 (q, 1H); 3.94 (s, 3H); 3.88 (s, 3H); 1.76 (d, 3H)).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[Li+]>C1(C)C=CC=CC=1>[C:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)([CH3:27])([CH3:25])[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
4-Bromo-3-methyl-benzoic acid (2.06 g, 9.6 mmol) and thionyl chloride (2.2 ml, 30.2 mmol) in toluene (50 ml) were heated at reflux for 2 h then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in THF (100 ml) and triethylamine (2.8 ml, 20.1 mmol), cooled down to 0° C. and lithium tert-butoxide (1.24 g, 15.5 mmol) was added portionwise. The mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% EtOAc:95% pet. ether) to yield the title compound (1.86 g, 71%).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=O)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[Br:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[CH2:2])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH:8]=1
Reactant: O=c1c2ccccc2cc(Br)c2ccccc12
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1c2ccccc2C=C(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a glove box, methyltriphenylphosphonium bromide (8.22 g, 23 mmol, 357.23 g/mol) was dissolved in 150 mL of THF in a flame-dried flask, and n-BuLi (9.21 mL, 23 mmol, 2.5 M in hexane) was added drop wise. The yellow mixture was stirred at ambient temperature for 30 min. and 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one (6.55 g, 23 mmol, 285.14 g/mol) was added as a THF solution. The mixture was stirred and heated at reflux for two days. The cooled solution was taken out of glove box and diluted with 100 mL of hexane. A small amount of water was added to quench the excess reagent, and the mixture was filtered through a plug of silica gel. The silica was rinsed with additional hexane, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel and eluted with ether/hexane (1:1) mixture by volume. Solvent was removed to yield 5.53 g (85 percent, 283.17 g/mol) of the title compound as a pale yellow oil that crystallized upon standing.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([OH:23])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](OC(OC(C)C)N(C)C)([CH3:26])[CH3:25].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(C(OCC)=O)C1)=O)CCC>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: O=C(O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OCC)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CC(C)OC(=O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The title compound is prepared analogously to Example 1s) starting from 1.87 g of N-benzyloxycarbonyl-1,2,3,4-tetrahydroquinoline-3(R,S)-carboxylic acid and 5.1 ml of N,N-dimethylformamide diisopropyl acetal Rf (A)=0.78; MS: (M)+ =353.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[N:21]=[C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]4[CH:29]=3)=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[H-].[Na+].CN(C)C=O.[C:37]([O:40][CH2:41][CH3:42])(=[O:39])[CH3:38]>>[CH3:28][C:26]1[CH:25]=[CH:24][N:23]2[CH:29]=[C:20]([C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:5]4[CH:4]=[C:3]([CH:1]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[O:39])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=4)[CH2:13][CH2:14]3)=[O:19])[N:21]=[C:22]2[CH:27]=1
Reactant: Cc1ccn2cc(C(=O)N3CCN(c4ccc([N+](=O)[O-])c(C=O)c4)CC3)nc2c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc(N2CCN(C(=O)c3cn4ccc(C)cc4n3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3-formyl-4-nitrophenyl)-4-(7methylimidazo[1,2-a]pyridine-2-carbonyl)piperazine (22.8 g), triethyl phosphonoacetate (15.6 g), sodium hydride (60% dispersion in mineral oil) (2.92 g) and N,N-dimethylformamide (250 ml) were stirred for 5 hours at ambient temperature. Ethyl acetate (250 ml) was added thereto and the resulting precipitates were collected and washed with ethyl acetate (100 ml) to give ethyl 3-[3-[4-(7-methylimidazo[1,2-a]pyridine-2-carbonyl)-1-piperazinyl]-6-nitrophenyl]acrylate (18.70 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[NH:31][C:30]([NH2:33])=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:18]1[CH:19]=[CH:20][N:16]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[N:31]=[C:30]([NH:33][C:13]([C:8]3[N:9]=[CH:10][C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)=[O:15])[NH:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: COc1ccc2cc(C(=O)O)ncc2c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc2c1
Yield: 84 %

Procedure:
71.8 mg (84%) of 7-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to General Procedure A using 41 mg (0.2 mmol) of 7-methoxy-isoquinoline-3-carboxylic acid, 48 mg (0.2 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 100 mg (0.246 mmol) of HBTU, 0.07 mL (0.4 mmol) of DIEA and 2 mL of DMF stirring at 80° C. for 2 h. LCMS: 428 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[CH:3]=1.[N:11]([O-])=[O:12].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N:11]=[O:12]
Reactant: Cc1cc(N)n(CCO)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(CCO)c(N)c1N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
5-Amino-1-(2-hydroxyethyl)-3-methylpyrazole (Bull. soc. chim. France, 255 (1975)) (1.41 g, 10 mmoles) was dissolved in a mixture of water (7 ml) and glacial acetic acid (1.4 ml). Sodium nitrite (0.8 g, 11.6 mmoles) in water (7 ml) was added dropwise over 0.5 hour at 0° C. The red solution was stirred at 0° C., and after 1 hour, the solid which had precipitated was filtered off and dried in vacuo giving the title compound as a red solid (1.2 g, 70%).
Reaction SMILES: C([O:9][CH:10]1[CH2:23][CH2:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([Br:24])=[CH:17][CH:18]=3)[C:13](=[O:25])[C:12]=2[CH2:11]1)(=O)C1C=CC=CC=1.O1CCCC1.[OH-].[K+]>CO>[Br:24][C:16]1[CH:15]=[C:14]2[C:19]([O:20][C:21]3[CH2:22][CH2:23][CH:10]([OH:9])[CH2:11][C:12]=3[C:13]2=[O:25])=[CH:18][CH:17]=1
Reactant: O=C(OC1CCc2oc3ccc(Br)cc3c(=O)c2C1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c2c(oc3ccc(Br)cc13)CCC(O)C2
Reaction time: 2 h
Yield: 80 %

Procedure:
45.0 g of 2-benzoyloxy-7-bromo-1,2,3,4-tetrahydro-9-oxo-xanthene obtained in Example 4 was suspended in a mixed solution of 240 ml of tetrahydrofuran and 90 ml of methanol. To the suspension was added dropwise at room temperature 45 ml of an aqueous solution containing 7.0 g of potassium hydroxide. After stirring the resulting solution for two hours, the solvent was removed by distillation. To the thus obtained crystals was added 300 ml of water, and the mixture was thoroughly agitated and filtered. The filtrate was recrystallized from ethanol to obtain 26.6 g (yield: 79.8%) of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-oxo-xanthene as light yellowish prism-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C=O)C>[CH2:31]([C:30]1[N:38]=[C:13]([CH:12]=[CH:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:15][N:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: N=C(Cc1ccccc1)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 2.0 g, 9.6 mmol) was dissolved in DMF (20 mL) to which 1,1′-carbonyldiimidazole (CDI) (1.71 g, 10.56 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-2-phenyl-acetamidine (1.58 g, 10.56 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After the completion of the reaction, additional CD (1.71 g, 10.56 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 8 h to effect cyclodehydration. DMF was evaporated and the residue obtained was cooled to room temperature followed by addition of water (15 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:9]O)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](=[S:13])=[S:12]>[OH-].[K+].O>[C:1]1([C@H:7]2[CH2:9][S:13][C:11](=[S:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: S=C1N[C@@H](c2ccccc2)CS1
Temperature: 110 °C
Yield: 8.7 %

Procedure:
To a solution of (S)-(+)-2-Phenylglycinol(1.40 g, 10 mmol) in 1N KOH/H2O (10 ml) at room temperature, was added carbon disulfide (3 ml, 50 mmol). The resulting solution was heated by a pre-heated oil-bath (110° C.) to reflux for 20 h after which the reaction mixture was cooled to room temperature and extracted with CH2Cl2 (3×30 ml), dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 as the eluting system (Rf=0.09, CH2Cl2:hexane=7:3) to obtain 4(S)-phenyl-thiazolidine-2-thione (170 mg, 9%).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>C(O)C(F)(F)F>[CH3:14][C:12]1[C:11](=[O:15])[O:10][CH2:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CCOC(=O)C(C)=O
Reactant: N[C@@H](CO)c1ccccc1
Solvent: OCC(F)(F)F
Product: CC1=N[C@H](c2ccccc2)COC1=O
Yield: 41 %

Procedure:
(R)-2-phenylglycinol (3.00 g, 21.9 mmol, 1.0 equiv.) and ethyl pyruvate (2.67 mL, 24.1 mmol, 1.1 equiv.) were refluxed in trifluoroethanol (50 mL) over activated 4 molecular sieves (8.00 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (7:3) to furnish the title compound as a white solid (1.70 g, 41%); mp 71.0-72.0° C. (lit 71.0-72.0° C.); v(max)(KBr) 3001 (C—H), 1734 (C═O), 1642 (C═N) cm−1; δH (250 MHz, CDCl3) 7.42-7.32 (5H, m, Ph), 4.89-4.80 (1H, m, PhCH), 4.56 (1H, dd, /4.49 Hz, T 11.55 Hz, 6β-H), 4.25 (1H, dd, J 10.97 Hz, T 11.51 Hz, 6α-H), 2.40 (3H, s, CH3); δC (62.5 MHz, CDCl3) 160.7, 155.9, 137.2, 129.4, 128.7, 127.5, 71.9, 60.1, 22.2; m/z (CL, NH3), 189 (M+, 25%), 159 (12%), 130 (24%), 104 (100%), 90 (21%), and 78 (6%); HRMS for C11H11NO2 requires 189.0787 found 189.0782. [α]D20 −2560.0 (c 1.11 CHCl3) (lit [α]D20 −237.1 (c 1.11 CHCl3)).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.CN(C)C=O.S(Cl)([Cl:33])=O.C>ClCCCl>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([Cl:33])=[O:12]
Reactant: O=C(O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 78.5 %

Procedure:
79.2 g of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid and 0.5 ml of dimethylformamide were introduced into 150 ml of 1,2-dichloro-ethane. 28.6 g of thionyl chloride were added dropwise at 60° to 65° C. and the mixture was heated under reflux for 1 hour. The solution was clarified with active charcoal and filtered through kieselguhr. The mother liquor was concentrated and the residue was recrystalllized from cyclohexane. 65.1 g (79% of theory) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzoic acid chloride, of melting point 95° C., were obtained.