Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([NH:15][C@H:16]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:17]([NH:19][N:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:21]1)=[O:18])=[O:14])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([NH:15][C@H:16]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:17]([NH:19][N:20]1[CH2:24][CH2:23][C@H:22]([N:25]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:21]1)=[O:18])=[O:14]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2CCCN2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, (50.0 mg, 0.081 mmol) in DCM (2 mL) was added TFA (2 mL). After the reaction solution was stirred at rt for 30 min. the solvent was removed in vacuo, and the residue was purified by HPLC to give the title compound (50.0 mg, 98.2%).
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH:10]([C:11]2[CH:40]=[CH:39][CH:38]=[CH:37][C:12]=2[C:13]([N:15]([CH:34]=[N:35][NH2:36])[CH2:16][CH:17]([P:26]([O:31]CC)(=[O:30])[O:27]CC)[P:18]([O:23]CC)(=[O:22])[O:19]CC)=[O:14])[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3].Br[Si](C)(C)C>O1CCOCC1.CO.O>[CH3:1][S:2]([CH:5]1[CH:10]([C:11]2[CH:40]=[CH:39][CH:38]=[CH:37][C:12]=2[C:13]([N:15]([CH:34]=[N:35][NH2:36])[CH2:16][CH:17]([P:18]([OH:22])(=[O:19])[OH:23])[P:26]([OH:31])(=[O:27])[OH:30])=[O:14])[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOP(=O)(OCC)C(CN(C=NN)C(=O)c1ccccc1C1CCNCC1S(C)(=O)=O)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)C1CNCCC1c1ccccc1C(=O)N(C=NN)CC(P(=O)(O)O)P(=O)(O)O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.5 g (2.4 mmol) of tetraethyl 2-[(3-methylsulfonyl-4-piperidylbenzoyl)-(aminoiminomethyl)amino]ethane-1,1-bisphosphonate from Example 1 are dissolved in 60 ml of absolute dioxane at 60° C. The reaction mixture is subsequently allowed to reach room temperature, and 1.64 g (10.8 mmol) of bromotrimethylsilane are added. The mixture is stirred at room temperatures for 16 hours and subsequently heated at 60° C. for a further 4 hours. Solvent and volatiles are subsequently removed at 40° C./0.1 torr. 15 ml of water are then added to the residue, and the mixture is stirred at room temperature for 4 hours. The resulting residue is filtered off and washed several times with ethanol. The residue resulting from this is subsequently boiled in 20 ml of methanol and 10 ml of water.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].BrCC1OC(C(F)(F)F)=CC=1.[F:18][C:19]1[C:20]([F:37])=[CH:21][C:22]2[O:36][CH2:35][C:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[C:23]=2[CH:24]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:18][C:19]1[C:20]([F:37])=[CH:21][C:22]2[O:36][CH2:35][C:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[C:26]3=[O:34])[C:23]=2[CH:24]=1
Reactant: CC(C)CCBr
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)CCN1C(=O)C2(COc3cc(F)c(F)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 1-bromo-3-methylbutane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, 5,6-difluoro-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (96%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (t, J=7.7 Hz, 1H), 7.16-7.04 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.77 (dd, J=10.3, 6.3 Hz, 1H), 6.50 (t, J=8.5 Hz, 1H), 4.95 (d, J=9.1 Hz, 1H), 4.70 (d, J=9.1 Hz, 1H), 3.88-3.67 (m, 2H), 1.72-1.60 (m, 3H), 1.01 (d, 6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ176.3, 156.6 (d, JC-F=11.0 Hz), 151.1 (dd, JC-F=248.1, 14.5 Hz), 145.6 (dd, JC-F=241.3, 14.0 Hz), 142.3, 131.6, 129.2, 123.8, 123.3, 111.5 (d, J=20.5 Hz), 108.7, 99.9 (d, J=22.3 Hz), 80.7, 57.7, 38.8, 36.0, 26.0, 22.4, 22.3; MS (ES+) m/z 344.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[CH:3]=1.[O:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][CH:17]3[CH2:16][CH2:15][O:14][CH2:19][CH2:18]3)=[CH:22][CH:23]=2)=[CH:3][C:4]1=[O:13]
Reactant: CC(C)CCn1ccc(Br)cc1=O
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)cc2)OC1(C)C
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
Product: CC(C)CCn1ccc(-c2ccc(NC3CCOCC3)cc2)cc1=O
Temperature: 150 °C
Yield: 98.9 %

Procedure:
A suspension of intermediate D4 (0.46 g, 1.9 mmol), intermediate D7 (0.69 g, 2.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.19 mmol) in a mixture of dioxane (4 ml) and saturated aqueous sodium carbonate (4 ml) was heated at 150° C. for 10 minutes, under microwave irradiation. The crude was filtered over diatomaceous earth and washed with EtOAc. The organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 and finally EtOAc as eluent). The desired fractions were collected and evaporated in vacuo to yield D8 (0.64 g, 95%) as a yellow solid.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)[NH2:2].[C:13](=S)=[S:14].C(N(CC)CC)C.S>N1C=CC=CC=1>[N:1]1[N:2]=[C:13]([SH:14])[N:4]2[N:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=12
Reactant: NNc1nncc2ccccc12
Reactant: S=C=S
Agent: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Sc1nnc2c3ccccc3cnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In pyridine, was dissolved 25 g of 1-hydrazinophthalazine. Thereto, 13 g of carbon disulfide was added dropwise at a temperature of 0° C. The stirring was continued for 30 minutes and then, the temperature of the reaction mixture was raised to 50° C., and the stirring was continued for additional 1 hour. Thereafter, the temperature was lowered to 0° C. again. Upon the addition of excess triethylamine to the resulting solution, hydrogen sulfide gas began to evolve. The temperature of the reaction system was raised and the refluxing was continued for 3 hours. Thereupon, the evolution of the gas ceased, and the reaction system was cooled. Upon cooling, crystals separated out. The crystals were filtered off, and recrystallized from ethanol. Yield 23 g, Melting Point 270°-280° C.
Reaction SMILES: [F:1][C:2]([F:28])([C:17]1([OH:27])[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[CH:14]=[C:13]([CH2:15][OH:16])[O:12][N:11]=1)=[O:4].Br.Br[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P(C(C)(C)C)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:28][C:2]([F:1])([C:17]1([OH:27])[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH2:22]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[CH:14]=[C:13]([CH2:15][O:16][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)[O:12][N:11]=1)=[O:4]
Reactant: Brc1ccnnc1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(CO)on2)C1
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COc3ccnnc3)on2)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A sealed tube was charged with a mixture prepared by adding toluene (2 ml) to Compound 18 (30 mg), 4-bromopyridazine hydrobromide (22 mg), Pd(OAc)2 (2 mg), Cs2CO3 (37 mg), and [1,1′-binaphthalen]-2-yldi-tert-butylphosphine (3 mg) and the mixture was stirred at 100° C. for 4 hours. After cooling the reaction mixture to room temperature, NH silica gel was added, followed by stirring for a while. After separating the silica gel by filtration, the silica gel was washed with chloroform and the solvent was distilled off; the resulting residue was purified by reverse-phase preparative HPLC to give the titled compound (6.0 mg, colorless oil.)
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13](=[O:19])[C:14]2[S:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[CH2:6][CH:7]([CH:9]=[O:10])[O:8][C:4]=2[C:3]=1[Cl:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32](O)[CH2:33][OH:34]>C1C=CC=CC=1.O>[CH2:33]1[O:34][CH:9]([CH:7]2[CH2:6][C:5]3[CH:11]=[C:12]([C:13](=[O:19])[C:14]4[S:18][CH:17]=[CH:16][CH:15]=4)[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=3[O:8]2)[O:10][CH2:32]1
Reactant: OCCO
Reactant: O=CC1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C1OCCO1)C2
Reaction time: 3 h

Procedure:
A benzene mixture (250 ml.) containing 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde (3.2 g., 0.01 mole), p-toluenesulfonic acid (0.2 g.) and ethyleneglycol (15 ml.) is heated under reflux for three hours. The water formed in the reaction is co-distilled with the benzene and is removed by a Dean-Stark apparatus. After three hours, the reaction mixture is cooled, washed twice with dilute sodium bicarbonate (2×50 ml.) once with water (50 ml.) and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give the 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde ethyleneacetal.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C([Cl:8])=O.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C@@H:24]2[CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].C(N(CC)CC)C>ClCCl.O>[ClH:8].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]2[CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCC[C@@H](O)[C@@H]1CN1CCCC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C1CN1CCCC1
Temperature: 20 °C
Reaction time: 0.05 h
Yield: 77.4 %

Procedure:
Dimethylsulphoxide (0.925 g) in dry dichloromethane (3 ml) was added dropwise to a stirred solution of oxalyl chloride (0.753 g) in dichloromethane (12 ml) at -60° under nitrogen, so as to maintain the internal temperature below -50°. The reaction mixture was stirred for 3 min before adding a solution of the product of Example 4 (2.0 g) in dichloromethane (5 ml) over 5 min. Stirring was continued for 15 min at -60° and triethylamine (2.72 g) was added with stirring. The reaction mixture was allowed to warm to 20° C., water (30 ml) was added, the layers were separated and the aqueous layer was further extracted with dichloromethane (30 ml). The combined organic extracts were dried and concentrated in vacuo to give a solid which was triturated under dry diethyl ether to give the free base of the title compound as an amorphous solid (1.54 g), m.p. 74°-76°. A portion (100 mg) of the free base was dissolved in a minimum amount of diethyl ether/ethyl acetate and treated with ethereal hydrogen chloride to precipitate the title compound as an amorphous solid (85 mg) m.p. 145°-147° (decomp.)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[CH:6][N:5]=[C:4]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:3]=12
Reactant: CN(C)C(=O)c1cncc(-c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1cncc(-c2cnc3[nH]cc(-c4ccccc4F)c3c2Cl)c1
Reaction time: 10 h
Yield: 33 %

Procedure:
5-[4-chloro-3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide was taken up in dichloromethane and 500 μL of trifluoroacetic acid added. The mixture was left at ambient temperature for 10 h and then evaporated. The residue was re-dissolved in 3 mL of dichloromethane and 100 μL of 1,2-ethylenediamine. After 6 h at ambient temperature the mixture was evaporated to dryness. The resulting crude was dissolved in dimethylsulfoxide and purified by mass-triggered reverse phase HPLC to afford 18.2 mg (46 μmol, 33%) of 5-[4-chloro-3-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide as an off-white solid. 1H-NMR [500 MHz, d6-DMSO] δ: 12.50 (s, br., 1H), 8.73 (d, 1H), 8.65 (d, 1H), 8.32 (s, 1H), 7.97 (t, 1H), 7.76 (s, 1H), 7.47 (ddd, 1H), 7.41 (, 1H), 7.28-7.21 (m, 2H), 3.01 (s, 3H), 2.97 (s, 3H); MS [MH+] m/z: 395.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]([F:13])([F:12])[C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7]>O1CCCC1>[CH3:1][O:2][C:6]1([C:5]([F:13])([F:12])[F:4])[O:8][CH2:9][CH2:10][O:7]1
Reactant: O=C(OCCCl)C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 4 h
Yield: 43 %

Procedure:
A suspension of 5.4 g (0.10 mol) of sodium methoxide in 50 mL of tetrahydrofuran (THF) was stirred at -20° to -10° while 17.7 g (0.10 mol) of 2-chloroethyl trifluoroacetate were added dropwise. The resulting clear solution was allowed to warm with precipitation commencing at about 10° and a slow exotherm ensuing to 35° . The mixture was maintain below 35° until the exotherm subsided and then was stirred for 4 h. Filtration and fractionation of the filtrate gave 7.4 g (43% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 61°-62° at 3.3 kPa (25 mm). IR (neat): 3000, 2965, 3 2925, and 2680 (sat,d CH), 1250-1100 cm-1 (CF, C--0). NMR (CCl4): 1H 4.17 (m, 4H, ring CH2 and 3.33 ppm (s, 3H, OCH3); 19 F-85.0 ppm (s, CF3).
Reaction SMILES: CN(CCN(C)C)C.C([Li])(C)(C)C.[CH3:14][C:15]1([CH3:63])[O:19][C:18]2[C:20]([C:29]([C:47]3[C:57]4[O:58][C:59]([CH3:62])([CH3:61])[O:60][C:56]=4[CH:55]=[C:49]4[O:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=34)([C:31]3[C:41]4[S:42][C:43]([CH3:46])([CH3:45])[S:44][C:40]=4[CH:39]=[C:33]4[S:34][C:35]([CH3:38])([CH3:37])[S:36][C:32]=34)[OH:30])=[C:21]3[O:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]3=[CH:28][C:17]=2[O:16]1.[C:64](=[O:66])=[O:65]>C1CCCCC1.CCOCC>[C:64]([C:28]1[C:22]2[O:23][C:24]([CH3:26])([CH3:27])[O:25][C:21]=2[C:20]([C:29]([C:47]2[C:48]3[O:52][C:51]([CH3:54])([CH3:53])[O:50][C:49]=3[C:55]([C:24]([OH:25])=[O:23])=[C:56]3[O:60][C:59]([CH3:62])([CH3:61])[O:58][C:57]=23)([C:31]2[C:32]3[S:36][C:35]([CH3:37])([CH3:38])[S:34][C:33]=3[C:39]([C:15]([OH:19])=[O:16])=[C:40]3[S:44][C:43]([CH3:45])([CH3:46])[S:42][C:41]=23)[OH:30])=[C:18]2[C:17]=1[O:16][C:15]([CH3:63])([CH3:14])[O:19]2)([OH:66])=[O:65]
Reactant: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4SC(C)(C)S6)SC(C)(C)S5)c2O1)OC(C)(C)O3
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)O)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c(c2C(=O)O)OC(C)(C)O3)O1
Reaction time: 0.33 h

Procedure:
Dry TMEDA (1.21 mL, 8.04 mmol) and t-butyllithium (5.36 mL, 1.5M in pentane) were dissolved in dry cyclohexane (12 mL) at 0° C. Bis-(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxol-4-yl)-mono-(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)methanol (0.608 g, 0.804 mmol) was then added at ambient temperature as a solid. After 20 min, solid carbon dioxide was added followed by dry ether (50 mL). After stirring for 17 h, the reaction mixture was filtered and the precipitate was dried. The acid was purified by preparative HPLC. Yield 0.285 g (40%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH2:15]([S:17]([C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1)([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:16].C(=O)([O-])[O-].[K+].[K+].C(O)(C)(C)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH2:15]([S:17]([C:20]([C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH2:6][CH2:5]3)[CH:26]=[N:27][CH:28]=1)([CH3:22])[CH3:21])(=[O:18])=[O:19])[CH3:16]
Reactant: Brc1ccc2c(c1)CCc1nncn1-2
Reactant: CCS(=O)(=O)C(C)(C)c1cncc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCS(=O)(=O)C(C)(C)c1cncc(-c2ccc3c(c2)CCc2nncn2-3)c1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 22 Step B (0.020 g, 0.080 mmol), the title compound from Example 62 Step E (0.021 g, 0.080 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.132 mg, 1.599 μmol), and potassium carbonate (0.033 g, 0.240 mmol) were added tert-butanol (0.90 mL) and water (0.10 mL). The vial was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with acetonitrile and then purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 N hydrochloric acid solution was added and the solution concentrated to provide the title compound: LCMS m/z 382.99 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 9.42 (s, 1H), 8.97 (s, 1H), 8.83 (s, 1H), 8.29 (s, 1H), 7.93-7.91 (m, 2H), 7.85-7.83 (m, 1H), 3.18-3.13 (m, 4H), 2.96 (q, J=7.43 Hz, 2H), 1.87 (s, 6H), 1.07 (t, J=7.43, 3H).
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]4[CH:30]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:31]1([C:37]2[CH:42]=[C:41](B(O)O)[CH:40]=[C:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[C:31]1([C:37]2[CH:42]=[C:41]([C:2]3[C:3]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[N:23]=[C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][N:25]6[CH:30]=5)=[CH:18][CH:17]=4)=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[CH:40]=[C:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:38]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3cn4ccccc4n3)cc2)c2ccccc12
Reactant: OB(O)c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cc(-c3ccccc3)cc(-c3c4ccccc4c(-c4ccc(-c5cn6ccccc6n5)cc4)c4ccccc34)c2)cc1
Yield: 72.9 %

Procedure:
Two point five grams (5.5 mmol) of 2-[4-(10-bromo-anthracen-9-yl)-phenyl]-imidazo [1,2-a] pyridine, 1.6 g (5.8 mmol) of [1,1′;3′,1″] terphenyl-5′-boronic acid and 0.13 g of tetrakis (triphenylphosphine) palladium were dissolved into 20 milliliter of 1,2-dimethoxyethane, and adding 9 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 8 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 2.4 g of yellowish white solids (yield: 71%). As a result of mass spectrum (MS) analysis, the yellowish white solids were identified as the aimed substance, and it was recognized that m/e=598 for molecular weight of 598.24.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:13][C:14]([OH:16])=O)[C:4]1=[O:17])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:23]1([C:31](=[O:32])[NH:30][C:29](=[O:33])[NH:28]1)[CH2:22]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:33]=[C:29]1[NH:28][C:23]2([CH2:22][C:21]3[C:25](=[CH:26][CH:27]=[C:19]([NH:18][C:14](=[O:16])[CH2:13][N:5]4[C:4](=[O:17])[CH:3]([CH2:1][CH3:2])[O:8][C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]4=5)[CH:20]=3)[CH2:24]2)[C:31](=[O:32])[NH:30]1
Reactant: CCC1Oc2ccccc2N(CC(=O)O)C1=O
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1Oc2ccccc2N(CC(=O)Nc2ccc3c(c2)CC2(C3)NC(=O)NC2=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-ethyl-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acid (0.2 mmol, 47 mg), 5′-amino-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (0.2 mmol, 43 mg) and DIPEA (0.6 mmol, 104.5 μl) in DMF (1 ml) was added HATU (0.2 mmol, 76 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=435.2; tR=2.71. H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.24 (q, 1H), 7.03 (d, 1H), 6.87-6.92 (m, 4H), 4.65 (q, 2H), 4.41 (q, 1H), 3.34 (q, 2H), 3.00 (q, 2H), 1.78 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](O)=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=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.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:36]=[CH:35]/[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc2cnn(-c3ccc(F)cc3)c2cc1C
Temperature: 110 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
(a)(b) 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-ol [(484 mg, 2.0 mmol; prepared as described in Example 105(c)] was dissolved in DCM (20 mL) and pyridine was added (0.16 mL, 2 mmol) followed by triflic anhydride (0.36 mL, 2.1 mmol). After 1 h, the reaction was washed with 1 M HCl and the aqueous layer was dried over MgSO4, filtered, and concentrated. The crude 1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yltrifluoromethanesulfonate was taken up in 20 mL DMF, transferred to a stainless steel pressure bomb, and treated with ethyl acrylate (200 mg, 2 mmol), triethylamine (0.28 mL, 2 mmol), and Pd(PPh3)2Cl2 (160 mg, 0.2 mmol) and heated at 110° C. for 6 h. The reaction was incomplete so additional ethyl acrylate (200 mg, 2 mmol) and Pd(PPh3)2Cl2 (160 mg, 0.2 mmol) was added and the reaction was sealed and heated for 16 h. The reaction was cooled, diluted with EtOAc, washed with brine, and the organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by MPLC using SiO2 and a 1:9 EtOAc/hexane to 1:1 gradient. Obtained 350 mg (54% yield, 2 steps) of (E)-ethyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylate. MS found: (M+H)+=325.