Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:20]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:8][CH:9]=1.[Li+].[OH-].Cl>CC#N>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:7]3[S:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COC(=O)Cc1ccc(-c2ccccc2NC(=O)c2ccccc2-c2cc(OC)c(OC)c(OC)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(-c2ccccc2C(=O)Nc2ccccc2-c2ccc(CC(=O)O)s2)cc(OC)c1OC
Yield: 99.3 %

Procedure:
Dissolve (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (58) (56 mg, 0.11 mmol) in MeCN (3.8 mL) at rt and add 1M aqu LiOH (760 μL, 0.76 mmol). Stir reaction mixture 18 h at rt. Quench reaction mixture (cooling bath) with 2 M aqu. HCl. Extract the mixture with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4 to obtain (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid (59) (55 mg, 99%) as a brown solid. 1H NMR (400 MHz, CDCl3): 3.76 (s, 6H), 3.80 (s, 3H); 3.83 (s, 2H); 6.32 (d, 1H, J=3.5 Hz); 6.60 (s, 2H); 6.78 (d, 1H, J=3.5 Hz); 7.07 (t, 1H, J=7.6 Hz); 7.23 (d, 1H, J=7.6 Hz); 7.32 (t, 1H, J=7.6 Hz); 7.36-7.54 (m, 3H); 7.69 (d, 1H, J=8.0 Hz); 8.43 (d, 1H, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[C:2]=1[Cl:1])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(C(=O)N3CCOCC3)C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a round bottom flask charged with tert-butyl (2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)carbamate (91 mg, 0.202 mmol) was added dichloromethane (1076 μl) and TFA (269 μl). The reaction mixture was stirred at room temperature 3 h. Excess TFA was removed by concentration in vacuo. The crude residue was free based using a Phenomenex Strata 1 g SCX column. The column was flushed with 3 column volumes methanol and 3 column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo to provide 3-amino-4-chloro-5-(2-(morpholine-4-carbonyl)morpholino)benzonitrile (68 mg, 0.194 mmol, 96%)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C(O[C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)C.[CH3:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=1[OH:35])=[O:28]>O1CCCC1>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:14](=[O:25])[CH2:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=2[OH:35])=[O:28])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCOC(=O)c1ccc(OC)c(OC)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)c2ccc(O)cc2O)cc1OC

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (335 mL, 400 mmol), 2,4-dihydroxy acetophenone, 14 (15.2 g, 100 mmol) in tetrahydrofuran (150 mL) and ethyl-3,4-dimethoxy benzoate, 7 (21 g, 100 mmol) in tetrahydrofuran (100 mL) were reacted to afford 21, 1-(3,4-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (37 g), which was cyclized with Dowex-H+ (15 g) in 2-propanol (250 mL) in a similar way as described for 22 to afford 27. Yield 15.4 g, (52%); mp 263-265° C.; MS (FAB) 299 (M++1); IR (KBr) 3452, 1625; 1H NMR (200 MHz, CDCl3+DMSO-d6) δ 9.83 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.5 Hz, 1.7 Hz, 1H), 6.83 (d, J=1.7 Hz, 1H), 6.43 (d, J=8.5 Hz, 1H), 6.34 (s, 1H), 6.30 (dd, J=9.7 Hz, 2.0 Hz, 1H), 6.08 (s, 1H), 3.35 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1B(O)O
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+]
Product: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[C:1]([NH:5][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 77 %

Procedure:
The preparation of Example 1 was repeated with the changes that tert-butyl amine (14.6 g, 0.200 mole) and 4-nitrobenzoyl chloride (18.6 g, 0.100 mole) were the starting reactants. This reaction produced 17.13 g of crystals of the desired product (77% yield), mp 162°-163° C. proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.257 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.878 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 6.097 ppm (bs, 1H; N-H); 1,500 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[NH:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([N:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH3:18])=[O:9]
Reactant: O=C(O)c1cc(Br)c(Cl)cc1O
Reactant: CNc1ccccc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Temperature: 60 °C
Yield: 44.7 %

Procedure:
Alternatively, a mixture of 5-bromo-4-chloro-2-hydroxybenzoic acid (5 g, 19.9 mmol), 2-methoxy-N-methylaniline (3.13 g, 22.9 mmol) and P2O5 (5.36 g, 37.8 mmol) in anhydrous xylene was heated at 60° C. for 2 hrs and then refluxed for 17 hrs. The mixture was concentrated and purified via silica gel flash column chromatography eluted with ethyl acetate in hexane (20%) to give 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (3.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]([CH3:25])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CNS(C)(=O)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N(C)S(C)(=O)=O)cc3F)CC2)c(C)c1
Yield: 89.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (624 mg) described in Preparation Example 114 and N-methylmethanesulfonamide (349 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (599 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Yield: 56.5 %

Procedure:
1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (1.1 g, 2.4 mmol), and potassium hydroxide (0.44 g, 7.8 mmol) in THF (25 mL) and water (25 mL), according to the procedure described in Step 4 of Example 5. Crystallization from methylene chloride/hexane yielded the title compound as a light yellow solid (0.596 g, 54%), mp: 141-142° C. Mass spectrum (+ESI, [M+H]+) m/z 440; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 7.7 (m, 2H), 7.6 (t, 3H, J=4.4 Hz), 7.25-7.35 (m, 6H), and 5.65 ppm (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24]Cl)[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CS(C)=O>[N:31]([CH2:24][C:22]1[N:23]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:26])[C:11]2[N:27]([CH3:30])[C:28](=[O:29])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)[S:20][CH:21]=1)=[N+:32]=[N-:33]
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CCl)cs4)ccc3n(C)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN=[N+]=[N-])cs4)ccc3n(C)c21
Temperature: 45 °C

Procedure:
400 mg (0.8 mmol) of compound A, 3-(4-bromophenyl)-6-(4-chloromethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 10 ml of DMSO. 160 mg (2.4 mmol) of NaN3 are added. The mixture is heated at 45° C. overnight. The mixture is allowed to return to ambient temperature. The reaction medium is poured into water, and the precipitate is filtered off and washed with water. The product is taken up in ethanol and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].[C:27](Cl)(=[O:29])[CH3:28].Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([C:27](=[O:29])[CH3:28])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)=O)cc2)cc1F

Procedure:
In a reactor were placed 141 g of 3-fluoro-4-octyloxybiphenyl and 400 ml of methylene chloride, to which was gradually added 94 g of anhydrous aluminum chloride at 0° C. or less under stirring and then was added dropwise 56 g of acetylchloride. After completion of dropwise addition, the mixture was stirred for 6 hours while increasing the temperature. The reaction solution was added to dilute hydrochloric acid, and the organic layer was washed with water and dehydrated over Glauber's salt. Subsequently, the solvent was distilled off. The remaining fraction was recrystallized with chloroform, to obtain 3-fluoro-4-octyloxy-4'-acetylbiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:33]C([O-])=O)([O:27][CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:29][CH:28]([O:27][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:27][CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29])=[O:33])[C:10]2=[O:24])[C:14]1=[O:16])=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(C)OC(=O)OC(=O)[O-]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCC(C)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(C)CCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
4.28 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione, 5.91 g 2-pentyl dicarbonate from Example B2, 0.40 g of 4-dimethylaminopyridine and 500 ml of dry tetrahydrofuran are mixed and the mixture is stirred at 55° C. for 4 hours. The suspension is filtered off with suction on a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure, and the residue is admixed with 50 ml of isopropanol. After 30 minutes the precipitate is filtered off with suction and washed with 15 ml of isopropanol, and the yellow product is dried under reduced pressure to leave 2.86 g (41% of theory) of 2,5-di-2-pentyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as yellow powder. NMR (CDCl3) [ppm]: 67 =7.65 ppm (d,4H), 7.46 (d,4H), 4.98 (m,2H), 1.67-1.35 (m,8H), 1.26 (d,6H), 0.88 (t,6H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=12.CN(C)[CH:34]=[O:35]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:21]([CH:34]=[O:35])=[CH:22][C:15]=12
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
n-Butyllithium (2.5M in hexanes, 3.56 mmol) was added dropwise to a solution of diisopropylamine (3.56 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. under nitrogen. The reaction was stirred for 30 minutes at −78° C. and then a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.97 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise via syringe. The resulting reaction was stirred at −78° C. for 2 h and then a solution of N,N-dimethylformamide (11.88 mmol) in tetrahydrofuran (1 mL) was added dropwise by syringe. The reaction was stirred at −78° C. for 2 h and then quenched with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 70-100% CH2Cl2/hexanes) afforded the title compound as a white solid (66%). ESMS [M+H]+: 365.0
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH3:25][C:26]1[CH:27]=[C:28]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]3[N:22]=[CH:23][N:24]=[C:4]3[CH:3]=2)[CH:29]=[C:30]([CH3:32])[CH:31]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Product: Cc1cc(C)cc(-c2cc3ncnn3c(NCCNc3ccc([N+](=O)[O-])c(N)n3)n2)c1

Procedure:
In analogy to the procedure described for Example 94, 39.9 mg (72% of theory) of the product are obtained as a solid starting from 50 mg (0.133 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 55A) by coupling with 19.9 mg (0.13 mmol) of (3,5-dimethylphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:16]1[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=3[CH:15]=2)=[CH:2][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: Nc1ccccn1
Reactant: Cn1c(=O)sc2ccc(C(=O)CBr)cc21
Product: Cn1c(=O)sc2ccc(-c3cn4ccccc4n3)cc21
Yield: 28.7 %

Procedure:
5-(Imidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (0.65 g) was prepared in the substantially same manner as that of Example 4 from 5-(2-bromoacetyl)-3-methyl-2-benzothiazolinone (2.3 g) and 2-aminopyridine (2.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1B(O)O)[CH3:15].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:17]2[C:18]([CH2:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:14][CH3:15])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)cc1OC
Reactant: CCc1cccc(CC)c1B(O)O
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: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-4-methoxy-nicotinic acid methyl ester (4.0 g, 19.8 mmol), 2,6-diethylphenyl boronic acid (7.0 g, 39.3 mmol), Na2CO3 (2M in H2O, 39 mL) and Pd(PPh3)4 (2.0 g, 1.7 mmol) in toluene (200 mL) is heated overnight at 80° C. under argon. On cooling, hexane (200 mL) is added and the organic layer separated. The organic layer is washed with 1N NaOH and water, dried (Na2SO4) and concentrated. The residue is purified by silica gel column (hexane/EtOAc 4:1) to give 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester. 1H NMR (CDCl3) 8.99 (s, 1H), 7.30 (m, 1H), 7.15 (d, 2H), 6.89 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.34 (m, 4H), 1.06 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=O)[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].[CH:16]([C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:20]=1[NH2:21])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]([CH:16]([CH3:18])[CH3:17])[C:20]=1[N:21]1[C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:13]1=[O:15])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 50 %

Procedure:
0.386 g of anhydride obtained by dehydrating 4-nitrophthalic acid (including 20% of 3-nitrophthalic acid) at a temperature of about 190° C., and 0.354 g of 2,6-diisopropylaniline were mixed, and reacted at a temperature of 180° C. for 4 hours. After the reaction was finished, the reaction mixture was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated and dried and solidified. Then, it was recrystallized by using a mixture of hexane and ethanol, to obtain 0.352 g (yield 50%) of the specified compound.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[C@H:11]([C:16]([OH:18])=[O:17])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[CH:32]=[CH:31][CH:30]=CC=1.S(=O)(=O)(O)O>C(O)CCC>[CH2:19]([N:10]1[C@H:11]([C:16]([O:18][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17])[C@H:12]([C:13]([O:15][CH2:27][CH2:32][CH2:31][CH3:30])=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)[C@@H]1[C@H](C(=O)OCCCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (35.4 g), benzene (500 ml), n-butanol (45 ml) and conc. sulfuric acid (5.0 g) was refluxed for 16 hours, cooled, washed successively with water, 5% aqueous sodium hydroxide and water, and then concentrated under reduced pressure to give oily product of di-n-butyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (39.5 g). IR (neat, cm-1): 2950, 1750, 1710, 1445, 1420, 1350, 1200, 1060, 1020, 960, 745, 695.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([O:25]C)=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:6]=1[CH3:38])=[O:4].CO.[OH-].[Li+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[C:6]=1[CH3:38])=[O:4]
Reactant: COC(=O)Cn1nc2n(c1=O)C(c1ccc(C#N)cc1)C(C(=O)OC)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of Intermediate 16 (108 mg, 0.21 mmol) in THF (1 mL), was added MeOH (1 mL) followed by lithium hydroxide (3 M in water, 68 μL, 0.21 mmol). The reaction mixture was stirred at RT for 2 hours, and then lithium hydroxide (3 M in water, 27 μL, 0.08 mmol) was added. After a further 1 hour stirring at RT, the reaction mixture was made acidic by addition of 1 M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a white solid (100 mg).