Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[C:28]([F:52])=[CH:29][C:30]([Cl:51])=[C:31]([CH:50]=1)[O:32][C:33]1[CH:47]=[CH:46][C:36]2[N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[S:39][C:35]=2[C:34]=1[C:48]#[N:49]>O1CCCC1.C(OCC)(=O)C>[Cl:51][C:30]1[C:31]([O:32][C:33]2[CH:47]=[CH:46][C:36]3[N:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[S:39][C:35]=3[C:34]=2[C:48]#[N:49])=[CH:50][C:27]([NH:26][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=2)=[C:28]([F:52])[CH:29]=1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cc(NC(=O)c3cccc(OC(F)(F)F)c3)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzoic acid (68 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90→60/40), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (85 mg, 65%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: O=[N+]([O-])c1ccncc1Nc1ccc2[nH]ncc2c1
Solvent: CCO
Product: Nc1ccncc1Nc1ccc2[nH]ncc2c1

Procedure:
A suspension of N-(4-nitro-3-pyridinyl)-1H-indazol-5-amine, N5 -oxide (7 g) in 250 ml ethanol containing 0.5 g platinum oxide was hydrogenated at 60 psi for sixty hours and thereafter filtered through Celite and concentrated to 3.3 g solid. This solid was purified by HPLC (silica, 25% methanol in dichloromethane) to give 2.1 g solid. This solid was recrystallized twice from acetonitrile to give 1.5 g crystals, m.p. 198°-199°
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(OC(C1ON=C(C2C=CC(N)=CC=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)noc1-c1ccccc1
Agent: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Product: CCOC(=O)c1c(-c2ccc(N)cc2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
The title compound was prepared using 3-(4-nitro-phenyl)-5-phenyl-isoxazole-4-carboxylic acid ethyl ester by the same procedure as described for the preparation of 3-(4-amino-phenyl)-isoxazol-5-carboxylic acid ethyl ester in Example 1. The reaction mixture was refluxed for 16 hours instead of heating at 80° C. for 3 hours. The crude product was purified by flash chromatography over silica gel with 10% EtOAc in chloroform to give the title compound in 74% yield. IR (KBr): 3374, 1712 (br), 1628, 1610, 1439; 1H NMR (DMSO-d6) δ: 1.15 (t, 3H), 4.20 (q, 2H), 5.57 (s, 2H), 6.63 (d, 2H), 7.34 (d, 2H), 7.53-7.62 (m, 3H), 7.75-7.89 (m, 2H); Mass (ES+), 309 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[NH2:9])=O)=[CH:4][CH:3]=1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=O>C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:8]([CH3:10])[N:9]=[C:15]([CH3:17])[C:14]=2[C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CN(N)C(=O)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(C)c1-c1ccc(F)cc1
Reaction time: 14 h
Yield: 43.7 %

Procedure:
A mixture of 4-fluoro-N-methylbenzohydrazide (5.0 g), ethyl acetoacetate (4.84 g) and ethanol (140 ml) was stirred for 14 hrs. with heating under reflux. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with hexane-ethyl acetate (4:1-1:1, v/v). This oil was dissolved in ethanol (50 ml), 1,8-diazabicyclo[5.4.0]-7-undecene (0.5 ml) was added, and the mixture was stirred for 4 hrs. with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give ethyl 5-(4-fluorophenyl)-1,3-dimethyl-1H-pyrazole-4-carboxylate (3.41 g, yield 44%) as colorless crystals.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC1(C)C(C)(C)OB([C:51]2[NH:59][C:58]3[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=3[CH:52]=2)O1.Br[C:63]1[CH:64]=[CH:65][CH:66]=[C:67]2[C:72]=1[N:71]=[C:70]([NH:73][CH:74]([CH3:76])[CH3:75])[N:69]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=1)[C:68]2=[O:83]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:76][CH:74]([NH:73][C:70]1[N:69]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=2)[C:68](=[O:83])[C:67]2[C:72](=[C:63]([C:51]3[NH:59][C:58]4[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=4[CH:52]=3)[CH:64]=[CH:65][CH:66]=2)[N:71]=1)[CH3:75]
Reactant: CC(C)Nc1nc2c(Br)cccc2c(=O)n1-c1ccccn1
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c(=O)n1-c1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
Pd2dba3 (8.67 mg, 9.46 μmol, Strem Chemicals, MA), K3PO4 (161 mg, 0.757 mmol), XPhos (9.02 mg, 0.019 mmol, Strem Chemicals, MA), and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (248 mg, 0.946 mmol, 609) was sealed in a 5 mL conical microwave tube and evacuated and backfilled with nitrogen 3×. 8-Bromo-2-(isopropylamino)-3-(pyridin-2-yl)quinazolin-4(3H)-one (68 mg, 0.189 mmol, 415d) was added as a solution in 1,4-dioxane (0.7 mL). Water (0.2 mL) was added, and the mixture was stirred at 80° C. for 2 h. The material was cooled to RT and concentrated under reduced pressure. It was taken up in DMSO, filtered, and purified by reverse-phase preparative HPLC using an Xbridge column, 0.1% TFA in CH3CN/H2O, gradient 5% to 50% over 12 min. The product fractions were dried in a Genevac EZ-2 evaporator at 55° C. The material was solublized in 1:1 MeOH:DCM, and the free base was generated using a Si-carbonate cartridge (Silicycle, pre-washed with MeOH). The filtrate was concentrated under reduced pressure to give 2-((1-methylethyl)amino)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-(2-pyridinyl)-4(3H)-quinazolinone as a pale yellow solid (6 mg, 7%). 1H NMR (DMSO-d6) δ ppm 12.11 (1H, br. s.), 8.70 (1H, d, J=4.5 Hz), 8.06-8.12 (1H, m), 8.04 (1H, d, J=8.2 Hz), 7.78 (1H, d, J=7.0 Hz), 7.59-7.65 (2H, m), 7.18 (1H, t, J=7.7 Hz), 7.08 (1H, s), 6.97 (1H, br. s.), 5.84 (1H, d, J=7.4 Hz), 4.18-4.29 (1H, m), 4.11 (1H, br. s.), 3.14-3.19 (2H, m), 2.86 (2H, t, J=6.9 Hz), 1.18-1.25 (6H, m). m/z (ESI, +ve) 415.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=1)([OH:16])[CH2:12]2)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[F:23][C:22]1[C:17]([C:11]2([OH:16])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncccc1F)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ncccc2F)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-(3-Fluoro-pyridin-2-yl)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.25 g, 0.775 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 5 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.225 g). 1H NMR (400 MHz, d6-DMSO): δ 9.4 (broad, 1H), 8.85 (s, 1H), 7.8-7.7 (m, 1H), 7.45 (m, 1H), 6.7 (broad), 4.05 (broad, 2H), 2.65-2.55 (m, broad, 2H), 2.45-2.40 (m, broad, 2H), 2.3-2.2 (m, broad, 2H), 2.0-1.9 (m, broad, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](O)=[C:26]([CH2:31][CH2:32][CH3:33])[CH:25]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][C:4]3[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=4)=[C:26]([CH2:31][CH2:32][CH3:33])[CH:25]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
Using the procedures in Example 15, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 4-(4-chlorophenoxy)-2-propylphenol.
Reaction SMILES: [CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:27])[N:22]([CH2:24][C:25]#[N:26])[N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.O>[CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:27])[N:22]([CH2:24][C:25]4[NH:30][N:29]=[N:28][N:26]=4)[N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)n(CC#N)n3)cc2C1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)n(Cc4nnn[nH]4)n3)cc2C1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 88.4 %

Procedure:
To 2.23 g of 2-n-butylsulfonylamino-5-[2-cyanomethylpyridazin-3(2H)-on-6-yl]indane dissolved in 45 ml of dimethylformamide were added 1.8 g of sodium azide and 1.5 g of ammonium chloride, and the mixture was stirred at 95° C. for 3.5 hours. After cooling, water was added to the reaction mixture, and the mixture was made acidic with 10% hydrochloric acid. Crystals precipitated were collected by filtration, dried and then recrystallized from methanol to obtain 2.19 g of 2-n-butylsulfonylamino-5-[2-(5-tetrazolyl)methylpyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C=O)C.O>[C:47]([O:46][C:44]([N:51]1[CH2:56][CH2:55][N:54]([C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]([F:10])([F:22])[F:21])[CH2:53][CH2:52]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
DIPEA (5.7 g, 44.30 mmol) was added drop wise to 2-trifluoromethyl benzoic acid (3.36 g, 17.72 mmol) in DMF (25 mL). EDCI (7.07 gm, 36.91 mmol) and HOBT (2.39 g, 17.72 mmol) were added consecutively and, after 15 minutes, N-Boc piperazine (2.75 g, 14.77 mmoles). The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 30:70 EtOAc:hexane as eluent) afforded 4-(2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester in 39% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=2)[N:3]=1.CC(=CC)C.Cl([O-])=[O:29].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:19]([O:18][C:16](=[O:17])[CH2:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[C:11]([C:12]([OH:29])=[O:13])=[CH:10]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of tert-butyl 2-(2-chloro-3-formylquinolin-6-yloxy)acetate (3.6 g, 11 mmol) in tert-butanol (150 mL) was added 2-methyl-2-butene (14.9 mL, 133 mmol) and a solution of sodium chlorite (8.27 g, 73.1 mmol) and sodium dihydrogenphosphate (8.10 g, 58.7 mmol) in water (50 mL). The reaction was allowed to stir at room temperature for 1 hour. The tert-butanol was removed in vacuo. The mixture was diluted with water (60 mL) and acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (3.7 g, 100%) as a white solid. +ESI (M+H) 338.1; 1H NMR (400 MHz, CD3OD, δ): 8.69 (s, 1 H), 7.89 (d, J=9.19 Hz, 1 H), 7.56 (dd, J=9.19, 2.74 Hz, 1 H), 7.34 (d, J=2.93 Hz, 1 H), 4.76 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(C)c2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccc(C(=O)O)cc1)c1ccccc1OCc1ccccc1
Yield: 67.7 %

Procedure:
Methyl 4-(1-(2-(benzyloxy)phenyl)ethoxy)benzoate (0.5 g, 1.4 mmol) was dissolved in THF (5 ml) and methanol (5 ml). The solution was treated with sodium hydroxide (1N, 6 ml) and the reaction heated at 60° for 3 hours. The solvent was removed at reduced pressure and the reaction mixture diluted with water and extracted with ethyl acetate. The aqueous phase was acidified (pH1) with concentrated HCl and extracted with ethyl acetate (3×). The organic phases were combined, dried (MgSO4) and evaporated to give the title compound as a white solid (0.33 g, 68%).
Reaction SMILES: CN(C)[C:3]1[CH2:10][CH2:9][C:8]2[C:4]=1[CH:5]=[CH:6][CH:7]=2.[CH:12]1([Li])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.O>O1CCCC1>[CH:12]1([C:3]2[CH2:10][CH2:9][C:8]3[C:4]=2[CH:5]=[CH:6][CH:7]=3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: [Li]C1C=Cc2ccccc21
Reactant: CN(C)C1=C2C=CC=C2CC1
Solvent: C1CCOC1
Solvent: O
Product: C1=CC2=C(C3C=Cc4ccccc43)CCC2=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A solution of 12.5 g (85 mmol) of 4-(dimethylamino)-5,6-dihydropentalene in 50 ml of tetrahydrofuran are admixed with a solution of 10.4 g (85 mmol) of indenyllithium in 20 ml of tetrahydrofuran. The reaction solution is stirred for 24 hours at room temperature and the reaction is stopped by addition of water. Extraction with diethyl ether, drying of the organic phases over MgSO4 and removal of the solvent under reduced pressure and subsequent recrystallization of the crude product from diethyl ether gives 13.9 g (75%) of 4-indenyl-5,6-dihydropentalene.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:12][N:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:22]=2)[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5]1=[O:11]
Reactant: Cn1cc(Br)n2cncc2c1=O
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)n2cncc2c1=O
Temperature: 25 °C
Yield: 18.8 %

Procedure:
A solution of compound from Example 129, step 1 (80 mg, 0.35 mmol), (3-methylsulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na2CO3 (106 mg, 1 mmol), Pd(PPh3)2Cl2 (30.0 mg) in dioxane (3 mL) and water (0.5 mL) was stirred at 120° C. for 18 h under N2. After cooling to room temperature, the mixture was filtered, concentrated and purified by prep-HPLC to give the title compound (20.0 mg, 20%). 1H NMR (Methanol-d4 400 MHz): δ 8.70-8.65 (m, 1H), 8.30-8.20 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.22 (s, 1H), 3.56 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+ 304.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(O[CH:27]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]1[O:29][C:30](=[O:32])[CH3:31])(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:6]([C@@H:27]2[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]2[O:29][C:30](=[O:32])[CH3:31])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
2-Chlorobenzimidazole (7.5 g) and N,O-bis(trimethylsilyl)acetoamide (18.3 mL) were suspended in acetonitrile (150 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature. To the mixture was added trifluoromethanesulfonic acid trimethylsilyl ester (17.9 mL), and the mixture was stirred for 15 minutes. To the reaction mixture was added 1,2,3,5-tetra-O-acetyl-D-ribofuranose (17.3 g), and the mixture was stirred at room temperature for 6 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10) to give the title compound (12.4 g).
Reaction SMILES: [C:1]([C:11]1[CH:20]=[CH:19][C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[O:18]=[C:16]1[NH:15][C:14]2[CH:19]=[C:20]3[C:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:2][C:1](=[O:10])[C:11]3=[CH:12][C:13]=2[O:17]1
Reactant: O=C(C=Cc1ccccc1)c1ccc2[nH]c(=O)oc2c1
Solvent: ClC(Cl)Cl
Product: O=C1C=C(c2ccccc2)c2cc3[nH]c(=O)oc3cc21
Temperature: 120 °C
Reaction time: 0.92 h

Procedure:
1000 g of polyphosphoric acid are placed in a 1000-ml round-bottomed flask equipped with a mechanical stirrer. 119.36 g (0.45 mol) of 6-cinnamoylbenzoxazolinone, described in Application FR 73/23,281, are dissolved with stirring at a temperature of 120° C., and stirring is continued for 55 min while this temperature is maintained. The reaction mixture is hydrolyzed by vigorous stirring in 5 volumes of ice-cold water, and the product is drained, washed with water until the washes are neutral and dried. The precipitate obtained, finely powdered, is suspended in chloroform and the mixture is brought to the boil for 2 hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH2:11])=[CH:5][C:4]=1[CH3:12].[OH-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][NH:11][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:5][C:4]=1[CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(CN)c(C)cc1CN
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CNCc2ccccc2)c(C)cc1CNCc1ccccc1

Procedure:
Separately, 32.8 parts of 1,4-diaminomethyl-2,5-dimethylbenzene and 100 parts of 20% caustic soda were heated at 80C. and reacted by adding 50.4 parts of benzyl chloride with stirring to obtain 50 parts of 1,4-bis(benzylaminomethyl)-2,5-dimethylbenzene, to which was then admixed 30 parts of octylphenoxyhexadecylethenoxyethylsulfate soda, 10 parts of a sperm oil alcohol-ethylene oxide adduct and 10 parts of isopropanol with stirring to obtain 100 parts of an emulsifier-incorporated composition.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[N:16]=[CH:15][N:14]=[C:10]3[N:11]=[CH:12][N-:13][C:9]=23)=[C:5]([N+:17]([O-:19])=[O:18])[N:4]=[CH:3]1.[Na+].CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@@H](C/C=C/C)C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O.C1C(CCNS(C2C=CC(Cl)=CC=2)(=O)=O)=CC=C(CC(O)=O)C=1.C(CCC(NC(O)C(NCCCCNCCCN)=O)=O)CCCNC(N)=N.Cl.C[C@H]1[C@@]2(O)O[C@H](C[C@H](OC)C(C)=CC=CC=C[C@@H](C)C[C@@H](C)C([C@H](OC)[C@H](O)C(C)=C[C@@H](C)C(C[C@@H]([C@@H](C[C@H]3C[C@@H](OC)[C@H](O)CC3)C)OC([C@H]3N(C(C2=O)=O)CCCC3)=O)=O)=O)CC1.C[C@H]1CC(C)=C[C@@H](CC=C)C(=O)C[C@H](O)[C@@H](C)[C@@H](/C(/C)=C/[C@H]2C[C@@H](OC)[C@H](O)CC2)OC(=O)[C@H]2N(CCCC2)C(=O)C(=O)[C@]2(O)O[C@@H]([C@@H](OC)C[C@H]2C)[C@@H](OC)C1>>[CH3:1][N:2]1[C:6]([S:7][C:8]2[N:16]=[CH:15][N:14]=[C:10]3[N:11]=[CH:12][NH:13][C:9]=23)=[C:5]([N+:17]([O-:19])=[O:18])[N:4]=[CH:3]1
Reactant: Cn1cnc([N+](=O)[O-])c1Sc1ncnc2nc[n-]c12
Agent: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Product: Cn1cnc([N+](=O)[O-])c1Sc1ncnc2nc[nH]c12

Procedure:
azathioprine sodium; cyclosporine; daltroban; gusperimus trihydrochloride; sirolimus; tacrolimus.