Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1>CS(C)=O.O>[O:9]1[C:10]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)C1CCCC(=O)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of trimethylsulfoxonium iodide (53.3 g, 242 mmol) in dry DMSO (300 mL) under N2, was added NaH (9.69 g, 242 mmol) portionwise over 30 min. This light yellow mixture was stirred at rt for 1 h The reaction mixture was cooled in an ice bath and treated with methyl 3-oxocyclohexanecarboxylate (29.0 g, 186 mmol) dropwise while maintaining a temperature at or below 27° C. The resulting reaction mixture was allowed to warm slowly to rt and stir overnight. The reaction was diluted with water and extracted with DCM. The combined organics were washed with water, dried over MgSO4, filtered, and concentrated to provide the crude title compound (31.8 g, 85% crude yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.71 (m, 1H), 2.65 (d, J=1.76 Hz, 2H), 2.00 (dd J=11.8, 13.6 Hz, 2H), 1.74-1.85 (m, 2H), 1.60-1.74 (m, 1H), 1.40-1.56 (m, 2H), 1.17-1.32 (m, 1H).
Reaction SMILES: ClC1C(=O)C2C(C(=[O:13])C=1Cl)=CC=CC=2.N([O-])=O.[Na+].[N+:19]([C:22]1[C:23](=[O:33])[C:24]2[C:29]([C:30](=[O:32])[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:21])=[O:20]>CO.O>[OH:13][C:31]1[C:30](=[O:32])[C:29]2[C:24]([C:23](=[O:33])[C:22]=1[N+:19]([O-:21])=[O:20])=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: O=C1C=C([N+](=O)[O-])C(=O)c2ccccc21
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([N+](=O)[O-])C(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of 2,3 -dichloro-1,4-naphthoquinone (6.83g; 0.03 mole) in methanol (40 ml) was stirred during the addition of a solution of sodium nitrite (6.9g; 0.1 mole) in water (50ml) and the mixture stirred at 80° C for 3 hours. Solution was attained after about 1 hr and the nitro naphthoquinone began to separate after 2 hrs. After cooling in ice and the yellow crystalline solid was filtered off, taken up in water (200ml), charcoalized and precipitated the product by addition of one-third the volume of concentrated hydrochloric acid, filtered off, washed well with 5N HCl and dried in vacuo over P2O5 /NaOH to give 5.30 g (81%) of material of m.p. 162°-163° C (d) which was identical to that prepared above.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Cl[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>O>[I:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
5-Iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (35, 3.4 g, 12.0 mmol) and 20 mL of N,N-dimethylformamide were combined in a round bottom flask and sodium hydride (350 mg, 8.8 mmol) was added at room temperature. After 20 minutes, chloro-triisopropyl-silane (36, 1.9 mL, 8.8 mmol) was added. The reaction was stirred for 2 hours, then poured into water and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography eluting with 0-25% ethyl acetate in hexane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (37, 1.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13])([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13]
Reactant: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc(N)c2C1=O

Procedure:
A mixture of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (5 mmol) and 10% Pd/C (250 mg) in dimethylformamide is hydrogenated under 60 psi of hydrogen in a Parr Type Shaker to afford 2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([NH:38]N)[CH:35]=[CH:36][CH:37]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(O)=O.CCOCC.ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:35]3[C:34](=[CH:33][C:32]([O:31][CH2:30][C:21]4[CH:22]=[CH:23][C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:20]=4)=[CH:37][CH:36]=3)[NH:38][C:10]=2[CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)CC(=O)CCc1ccc(Cl)cc1
Reactant: NNc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(C)(C)Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(4-chlorophenyl)-2,2-dimethyl-4-oxohexanoate (Step C, 2.8 g) in toluene (30 mL) and glacial HOAc (15 mL) was added portion-wise solid 3 (quinolin-2-ylmethoxy)phenylhydrazine (Step A, 3.2 g) and stirred at room temperature for 2 hours. The reaction mixture was diluted with Et2O (200 mL) , washed with 1N NaOH, H2O, dried (Na2SO4) and evaporated to give crude hydrazone which was immediately treated as follows: the crude hydrazone was dissolved in a mixture of PPE(15 mL) and 1,2-dichloroethane (30 mL) and stirred at 40° C. for 18 hours. The reaction mixture was cooled to 0° C. and carefully treated with 1N NaOH to bring to pH 9. The mixture was then extracted with ether, the extract was washed with H2O, dried (Na2SO4) and evaporated to give a residue, which was chromatographed in a column of flash silica gel (eluting with EtOAc-hexane 25:75) and isolating the most polar component as the title product as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Br:11]Br>O>[Br:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]#[N:10]
Reactant: N#CCc1ccccc1Cl
Reactant: BrBr
Solvent: O
Product: N#CC(Br)c1ccccc1Cl
Reaction time: 3 h
Yield: 96 %

Procedure:
2-(2-Chlorophenyl) acetonitrile (151.5 g, 1 mol) was heated to 110° C. in a three-necked flask, keep the temperature, bromine (176 g, 1.1 mol) was added dropwise over a period of 3 h and the mixture was reacted with constant stirring for another 3 h. The reaction mixture was cooled to below 30° C. and water (400 mL) was added and stirring continued for another 5 minutes to remove HBr and stand aside. The organic layer was separated and washed with small amount of 5% sodium bisulfite for 15 minutes with stirring. The organic layer was again separated and washed with water to near pH 7, and the brown oily product was obtained (225 g, 96% yield); bp: 107-110° C./15 mmHg. IR (cm−1): 2969, 2253, 1589, 1472, 1445, 1194, 1051, 765, 725, 646; 1HNMR (300 MHz, CDCl3): 7.83 (1H, m), 7.38-7.45 (4H, m), 5.87 (1H, s). The crude product was used directly for the next step.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:5][CH2:4]1
Reactant: COC1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: COC1CCN(C(=O)CC(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
15 g (0.13 mol) of 4-methoxy-piperidine were added dropwise to a solution of 10.4 g of diketene (0.12 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 17.0 g (0.085 mol, 71% yield) of a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:18])=[CH:5][C:6]([OH:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:2].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[C:8]([C:7]1[C:6]([OH:17])=[CH:5][C:4]([O:18][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[C:3]([CH2:1][CH3:2])[CH:16]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCc1cc(C(=O)c2ccccc2)c(O)cc1O
Reactant: N#CCCCCBr
Product: CCc1cc(C(=O)c2ccccc2)c(O)cc1OCCCCC#N
Yield: 38.2 %

Procedure:
Following the procedure of Example 16, 0.726 g of 5-ethyl-2,4-dihydroxybenzophenone and 0.53 g of 5-bromopentanenitrile were allowed to react and provided 0.37 g of the desired title product, m.p. =42°-44° C.
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=1[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[C:1]([NH:18][C:19]1[C:20](=[O:21])[CH:22]=[CH:23][C:24](=[O:26])[CH:25]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(O)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)NC1=CC(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
30 g of (7-2) thus obtained was dissolved in 600 ml of ethyl acetate. 60 g of manganese dioxide was then added to the solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered off at an elevated temperature, and the filtrate was then concentrated. The concentrate was recrystallized from acetonitrile to obtain 27 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[CH2:16][CH:17]1[CH2:32][CH2:31][CH2:30][C:19]2([O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20]2)[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[CH2:25]([N:21]1[CH2:20][C:19]2([CH2:30][CH2:31][CH2:32][CH:17]([CH2:16][NH:6][C:5]3[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:18]2)[O:23][C:22]1=[O:24])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)CN1CC2(CCCC(CBr)C2)OC1=O
Reactant: Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)CN1CC2(CCCC(CNc3cc(C(F)(F)F)ccc3[N+](=O)[O-])C2)OC1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
A solution containing 2-nitro-5-(trifluoromethyl)aniline (0.777 g, 3.77 mmol) and 7-(bromomethyl)-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (1.00 g, 3.14 mmol) in DMF (15 mL) was treated with cesium carbonate (3.07 g, 9.43 mmol) and stirred at 60° C. overnight. The cooled reaction mixture was diluted with saturated, aqueous ammonium chloride solution, and the product was extracted into DCM. The organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified on a 120 g silica gel column (10-60 EtOAc/hexanes; 65 mL/min elution; 254 nm detection) to afford the title compound (0.260 g, 19 yield). MS (m/z) 444.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)=[O:12].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[OH2:6].[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1)=[O:12]
Reactant: O=Cc1ccccc1B(O)O
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: O=Cc1ccccc1-c1cccc(C(=O)O)c1
Yield: 157.2 %

Procedure:
The general procedure described in Example 3 was used with 3-chlorobenzoic acid (157 mg, 1.00 mmol), 2-formylphenylboronic acid (225 mg, 1.50 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 10 h, 80° C. The product was isolated as a white solid (192 mg, 85%). Mp=164-167° C. 1H NMR (400 MHz, d4-MeOH, d6-DMSO) δ: 8.07 (m, 2H), 7.68 (m, 1H), 7.63-7.52 (m, 2H), 7.46 (m, 2H), 7.30 (m, 1H), 5.10 (s, 1H), 4.98 (br-s, 2H). 13C NMR (125 MHz, d4-MeOH, d6-DMSO) δ: 169.4, 142.1. 142.0, 137.0, 135.0, 131.9, 131.7, 131.2, 129.9, 129.8, 129.6, 128.9, 127.8, 103.6 [Ar—CH(OH)2] IR (neat, cm−1): 3066, 1694, 1260, 754.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[OH:11][CH2:10][C:9]1[CH:14]=[CH:15][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: COC(=O)c1ccc(CNC(C)=O)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(CO)cc1[N+](=O)[O-]
Yield: 87.2 %

Procedure:
A solution of methyl 4-acetamidomethyl-3-nitrobenzoate (20 g) and lithium borohydride (1.7 g) in tetrahydrofuran (200 ml) was stirred at 40-50° C. for 2.5 hr. The reaction mixture was poured into water (150 ml) and extracted with ethylacetate (100 ml×3). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (15.5 g). The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a pale-brown solid (13.5 g). The obtained solid was crystallized from ethyl acetate/ethanol/hexane (30:2:5) to give the title compound (12 g) as yellow white crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:2].C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)[CH3:2]
Reactant: CCNc1nc(CO)cs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCNc1nc(C=O)cs1

Procedure:
The reaction described in Preparation 44 was repeated, but using 4.4 g of 2-ethylaminothiazol-4-ylmethanol, 13.3 g of sulfur trioxide pyridine complex, 8.4 g of triethylamine and 60 ml of dimethyl sulfoxide, giving the title compound as pale brown prisms.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][NH:13][CH2:14][C:15]1[N:16]=[CH:17][N:18](S(N(C)C)(=O)=O)[C:19]=1[CH3:20].[C:27](Cl)(Cl)=[O:28].[Cl-].[Cl-].[Cl-].[Al+3].CO>ClCCl>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:27](=[O:28])[N:13]([CH2:14][C:15]3[N:16]=[CH:17][NH:18][C:19]=3[CH3:20])[CH2:12][CH2:11][C:3]1=2
Reactant: O=C(Cl)Cl
Reactant: Cc1c(CNCCc2cc3ccccc3n2C)ncn1S(=O)(=O)N(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[[[(1-methyl-1H-indol-2-yl)ethyl]amino]methyl]-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (140 mg) in dry dichloromethane (15 ml) was cooled to 5° and the mixture was stirred under nitrogen while phosgene (12% w/w solution in toluene; 1 ml) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, aluminium trichloride (60 mg) was powdered and added, and stirring was continued overnight. After this time methanol (1 ml) was added and the reaction mixture was adsorbed onto FCC silica and purified by FCC eluting with System A (150:8:1) to give the protected derivative of the title compound (42 mg), as a solid, identical (by t.l.c. and m.p.) to the product of Intermediate 27. Deprotection as described in either of Examples 25 or 26 gives the title compound.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[C:28]([O:32][C:33](=[O:60])[C:34]([S:37][C:38]1[S:39][CH:40]=[C:41]([CH2:43][CH2:44][N:45]([C:53]2[N:58]=[CH:57][C:56](Br)=[CH:55][N:54]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[N:42]=1)([CH3:36])[CH3:35])([CH3:31])([CH3:30])[CH3:29].[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([O:32][C:33](=[O:60])[C:34]([S:37][C:38]1[S:39][CH:40]=[C:41]([CH2:43][CH2:44][N:45]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:53]2[N:58]=[CH:57][C:56]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[CH:55][N:54]=2)[N:42]=1)([CH3:36])[CH3:35])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(N2CCOCC2)cn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (45 mg), 2-(di-tert-butylphosphino)biphenyl (29 mg) and sodium tert-butoxide (104 mg) were added to a 20 mL screw cap test tube substituted with nitrogen, and a solution of 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (550 mg) synthesized in Example 442-1 and morpholine (129 mg) in toluene (2.0 mL) was added thereto. The test tube was capped, and stirred at 110° C. for 8 hr. After cooling to room temperature, the solution was directly packed and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 2:1) to give the title compound (300 mg) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[CH2:25]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:42](=O)[NH2:43])[CH:39]=2)[CH2:34]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:25]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:42]#[N:43])[CH:39]=2)[CH2:34]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC1Cc2ccc(C(N)=O)cc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCC1Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Subsequently, 8.71 g (33.2 mM) of triphenylphosphine, 25 ml of carbon tetrachloride and 15 ml of THF were placed in 200 ml-three necked flask. Under stirring at room temperature, 4.55 g (16.6 mM) of the above-prepared 2-octyl-5-carbamoylindan was gradually added to the above mixture, followed by washing with 10 ml, of THF and stirring for 3 hours at 45°-50.4° C. to precipitate a crystal. After the reaction, the crystal was removed from the reaction mixture by filtration and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from methanol to obtain 4.24 g of 2-octyl-5-cyanoindan (Yield: 99.8%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CC(=O)Nc1sc(Cl)c(C)c1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1sc(Sc2ccccc2)c(C)c1C(N)=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Intermediate 6 (2-Acetylamino-5-chloro-4-methyl-thiophene-3-carboxylic acid amide) (1.16 g, 5 mmol) is mixed with benzenethiol (535 μL, 5.25 mmol) and Cs2CO3 (3.25 g, 10 mmol) in DMF (15 mL). The resulting mixture is stirred at 120° C. for 30 min, then diluted with water, affording a suspension which is left to stir at room temperature overnight. The solid is separated by filtration, the cake is dried, and the resulting solid is used as such.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[N:23]=C(Cl)C=[CH:20][N:19]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:1]([N:3]2[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[N:4]2)[CH:2]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCn1cc(C=O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(Cl)n2)cc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N-dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (×2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 2 as a white solid (5.47 g, 42%); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, J=5.4 Hz), 7.87 (1H, d, J=5.4 Hz), 2.59 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[Br:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:64]2[NH:68][N:67]=[C:66]([NH2:69])[N:65]=2)([CH3:63])[CH3:62])=[CH:57][CH:56]=1>C(#N)C>[Br:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:64]2[N:65]=[C:66]([NH2:69])[N:67]([C:21]([C:2]3([CH3:1])[CH2:17][C:10]4([N+:18]([O-:20])=[O:19])[C:9]5[C:4]([CH:3]3[C:16]3[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:23])[N:68]=2)([CH3:63])[CH3:62])=[CH:57][CH:56]=1
Reactant: CC(C)(c1ccc(Br)cc1)c1nc(N)n[nH]1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc(Br)cc1)c1nc(N)n(C(=O)C2(C)CC3([N+](=O)[O-])c4ccccc4C2c2ccccc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (31 mg, 0.10 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (20 mg, 0.15 mmol), and N-ethyl-N,N-diisopropylamine (0.15 mL) in anhydrous acetonitrile (1.5 mL) was added EDCI (39 mg, 0.2 mmol) at RT under argon. After the mixture was stirred at RT for 5 min, 5-[1-(4-bromophenyl)-1-methylethyl]-1H-1,2,4-triazol-3-amine (28 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT for 2 h and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 53 mg (93% yield) of the title compound as a white solid which was used as such for the subsequent step without further purification.