Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N+:43]([O-])=O)=[CH:5][C:6]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:7]([CH:37]=1)[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]1[C:28]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:27][C:24]([C:25]#[N:26])=[C:23]([N+:34]([O-])=O)[CH:22]=1)#[N:2]>CC(O)=O.CC(O)C.[Fe]>[NH2:43][C:4]1[CH:5]=[C:6]([O:38][CH2:39][CH2:40][O:41][CH3:42])[C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([NH2:34])[C:24]([C:25]#[N:26])=[CH:27][C:28]=2[O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:37][C:3]=1[C:1]#[N:2]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOC
Agent: [Fe]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COCCOc1cc(C#N)c(N)cc1OCCOCCOCCOCCOc1cc(C#N)c(N)cc1OCCOC
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of 4-(2-(2-(2-(2-(5-cyano-2-(2-methoxyethoxy)-4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)-2-nitrobenzonitrile (0.2 g) in AcOH (10 mL) and i-PrOH (10 mL) was added iron powder (0.5 g). The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was cooled to room temperature, filtered, the precipitate washed with EA (10 mL). The combined washings and filtrate were concentrated under reduced pressure and purification by silica chromatography to give 0.18 g of 2-amino-5-(2-(2-(2-(2-(5-amino-4-cyano-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)benzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 6.91 (s, 1H), 6.88 (s, 1H), 6.34 (s, 1H), 6.25 (s, 1H), 4.30 (br, 2H), 4.22-4.05 (m, 10H), 3.88-3.65 (m, 16H), 3.43 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:22][C:13]1[CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:17][C:12]=1[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(Br)c(F)c1
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: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)c(F)c1
Yield: 64.5 %

Procedure:
2′-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (0.30 g, 2.07 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.5 g, 1.98 mmol), 2M Na2CO3 (12 mL) and Pd(PPh3)4 (20 mg, 0.02 mmol) in DME (12 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H, Ja=8.0 Hz, Jb=1.5 Hz), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.47 (d, 2H, J=7.1 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.94 (bs, 1H), 3.10 (s, 3H); LRMS (ESI), m/z 267 (M+H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.2 %

Procedure:
A mixture of 2.8 g of methyl 5-benzimidazolecarboxylate (prepared as described in Preparation 26), 3.52 g of benzyl bromide, 3 g of potassium carbonate and 50 ml of acetone was stirred for 3 days at room temperature. At the end of this time, the solvent was removed by evaporation under reduced pressure and the residue was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was then recrystallized from a mixture of ethyl acetate and hexane, to give 0.94 g of the title compound, melting at 156°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[N:12][N:11](C3CCCCO3)[C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:20])[CH:9]=2)=[CH:21][CH:22]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Product: O=c1cc(OCc2ccc(Cl)cc2)cn[nH]1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a stirred suspension of 5-((4-chlorobenzyl)oxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (210 mg) in MeOH (5 ml) was added conc. HCl (0.5 ml) at room temperature, and then the reaction mixture was heated at reflux for 3 h. The mixture was cooled to room temperature, concentrated in vacuo and neutralized with saturated NaHCO3 (20 ml). The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (140 mg) as an off-white solid.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)(=O)=O.N[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CN1CCCC1=O>CCOC(C)=O.O>[O:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[CH:12][S:11][C:9]=3[N:10]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)c1ncc2ccsc2n1
Reactant: NCCN1CCOCC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1cc2cnc(CCN3CCOCC3)nc2s1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 2-(methylsulfonyl)thieno[2,3-d]pyrimidine (1.0 g, 4.67 mmol), 4-(2-aminoethyl)morpholine (1.8 g, 14.02 mmol), and 1-methyl-2-pyrrolidinone (1.5 mL) was heated to 100° C. overnight. The reaction mixture was cooled to RT and diluted with EtOAc (200 mL)/water (75 mL). The layers were separated, and the organic layer was washed successively with water (4×75 mL) and brine (1×75 mL). The organic layer was then dried over MgSO4, filtered and concentrated to give (1.2 g) of the crude product. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide the title compound (1.02 g) MS (ES+): 265 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[OH:33]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[OH:33])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Product: COC(=O)c1ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c(O)c1
Yield: 44.1 %

Procedure:
Using N-(tert-butoxycarbonyl)-D,L-alanine (3.74 g, 19.7 mmol), 2-methylpropyl chlorocarbonate (2.56 mL, 19.7 mmol) and methyl 4-amino-3-hydroxybenzoate (3.00 g, 19.7 mmol), a method in the same manner as in Reference Example 105 was performed, and the obtained residue was triturated with ethyl acetate to give the title compound (2.94 g, yield 48%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCc1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1cccc(CBr)n1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 6-methoxymethyl-2-pyridinemethanol (860 mg, 5.64 mmol) and triphenylphosphine (1.78 g, 6.77 mmol) in dichloromethane (40 mL) at 0° C. was treated portion wise with CBr4 (2.80 g, 8.43 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (1.20 g, 99%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.71 (1H, t, J 8.0 Hz), 7.35 (2H, d, J 8.0 Hz), 4.58 (2H, s) and 4.54 (2H, s).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCCO2
Yield: 77 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(chroman-6-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.094 g; 0.226 mmol), sodium hydroxide 10N (0.226 mL; 2.26 mmol) in methanol (2.2 mL) to afford 0.070 g (74%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[O:22]([CH2:29][CH2:30]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: BrCCOc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCOc2ccccc2)C1

Procedure:
A mixture containing 3-(R)-(1-cyano-1,1-diphenylmethyl)piperidine (0.3 g), 2-phenoxyethyl bromide (0.24 g--commercially available), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was then partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.254 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O-:19])(=[O:18])[CH:16]=[CH2:17].[CH2:20](N(CC)CC)[CH3:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1cc(-n2ncnn2)cc(I)c1N
Reactant: CCN(CC)CC
Reactant: C=CC(=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)/C=C/c1cc(-n2ncnn2)cc(C)c1N

Procedure:
The following compound, m.p. 162°-5°, was prepared similarly to the previous Preparation using 2-(4-amino-3-iodo-5-methylphenyl)tetrazole, ethyl, acrylate, palladium acetate and triethylamine as the starting materials: ##STR143##
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1NC2CCC1C2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C2CCC(C2)N1C(=O)c1ccc(OC)cc1
Yield: 73.6 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (181 mg, 1.07 mmol) obtained in Example 1 (b) in chloroform (2 ml) were added triethylamine (0.16 ml, 1.18 mmol) and 4-methoxybenzoyl chloride (201 mg, 1.18 mmol) while being cooled with ice. After a reaction at room temperature for 1 hour, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (25%–40% ethyl acetate/hexane), to give ethyl 2-(4-methoxybenzoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (239 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[N:5]=[C:4]2[S:12][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([CH3:15])[C:3]=12.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:15][C:14]1[C:3]2[C:2]([NH2:1])=[CH:7][C:6]([CH3:11])=[N:5][C:4]=2[S:12][C:13]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc2sc(-c3cccnc3)c(C)c2c(N)c1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(N)c2c(C)c(-c3cccnc3)sc2n1
Temperature: 200 °C
Yield: 53.9 %

Procedure:
A mixture of 4-amino-3,6-dimethyl-2-(3-pyridinyl)thieno[2,3-b]pyridine-5-carboxylic acid (98 mg, 0.327 mmol) (Description 33) and diphenyl ether (2 mL) was heated at 200° C. for 2.5 h. After cooling to RT, the mixture was purified by chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in cyclohexane then followed by 10% MeOH in DCM, to afford the title compound (45 mg). LCMS (A) m/z: 256 [M+1]+, Rt 0.61 min (acidic).
Reaction SMILES: N1(C(O[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]4[C:25]([C:26]5[C:27]([CH3:40])=[N:28][N:29]([CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)[C:30]=5[CH3:31])=[CH:24][NH:23][C:20]4=[N:21][CH:22]=3)[CH:12]=2)=O)CCCCC1>Cl.CO>[F:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:29]1[C:30]([CH3:31])=[C:26]([C:25]2[C:19]3[C:20](=[N:21][CH:22]=[C:17]([C:13]4[CH:12]=[C:11]([NH:10][CH:18]5[CH2:17][CH2:22][NH:21][CH2:20][CH2:19]5)[CH:16]=[CH:15][CH:14]=4)[CH:18]=3)[NH:23][CH:24]=2)[C:27]([CH3:40])=[N:28]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(NOC(=O)N4CCCCC4)c3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(NC4CCNCC4)c3)cc12
Yield: 48.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-((3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino piperidine-1-carboxylate (80 mg, 0.134 mmol) was deprotected in HCl in methanol (5 ml). This afforded 16 mg (20.4% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.8-8.6 (bs, 1H), 8.37 (s, 1H), 7.67 (s, 1H), 7.41-7.35 (m, 2H), 7.12-7.10 (m, 2H), 7.06-7.04 (m, 2H), 6.94-6.90 (m, 2H), 5.41 (s, 2H), 3.85-3.70 (m, 1H), 3.50-3.47 (m, 2H), 3.18-3.12 (t, 2H), 2.29-2.24 (m, 8H), 1.79-1.76 (m, 2H). MS: m/z=495.3 (M+1), HPLC: 85.03% in method A.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]2[C:10]([C:11]=1[I:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.S([O:21][CH3:22])(OC)(=O)=O.[C:23](=O)([O-])[O-].[K+].[K+].CC(C)=O>C(N(CC)CC)C>[CH3:23][O:1][C:2]1[C:3]([C:13]([O:21][CH3:22])=[O:15])=[CH:4][C:5]2[C:10]([C:11]=1[I:12])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc2ccccc2c(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccccc2c(I)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of 3-hydroxy-4-iodo-2-naphthoic acid (8.0 g), dimethyl sulfate (8.03 g), powdered potassium carbonate (8.80 g), and dry acetone (150 mL) was heated under reflux for 18 h. The solution was cooled to room temperature, triethylamine (15 mL) was added, and stirring continued for 30 min. The solution was filtered through a pad of Celite and washed with dry acetone (50 mL). The filtrate was concentrated to a yellow oil, diluted with EtOAc, and washed successively with 1N HCl (100 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). The organic phase was dried (sodium sulfate), filtered, concentrated, and purified by chromatography (0-10% EtOAc in hexanes) to afford the product as a yellow oil (5.53 g). 1H NMR (DMSO-d6) δ 8.47 (s, 1 H), 8.09 (m, 2 H), 7.74 (m, 1 H), 7.61 (m, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][CH2:19][C:20]#[N:21])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: N#CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (100 mg) in anhydrous DMF (1.0 ml) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-bromopropionitrile (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/chloroform=1/10) to obtain 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (94 mg). NMR (H1, CDCl3): δ 2.82 (2H, t, J=6.8 Hz), 4.24 (2H, t, J=6.8 Hz), 6.68 (1H, t, J=4.9 Hz), 7.06-7.10 (2H, m), 7.74-7.78 (2H, m), 8.35 (2H, d, J=4.9 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]1[C:20]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=2[N:22]=[CH:23][CH:24]=1>ClCCl>[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]1[C:20]2[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][NH:25][C:21]=2[N:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)c2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(C(F)(F)F)c23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 ml of trifluoroacetic acid are added to a solution of 182 mg (0.387 mmol) of N-(2-fluoro-4-nitrophenyl)-3-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine in 3.00 ml of dichloromethane, and the mixture is stirred at RT for 30 min. The solvents are removed under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with saturated solutions of sodium bicarbonate and sodium chloride, the organic phase is dried with magnesium sulfate and the solution is concentrated. The product is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:20][CH2:21][CH3:22])[C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][CH:12]=3)=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:20][CH2:21][CH3:22])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:17]2[CH3:18])([CH3:29])[CH3:28])[CH3:24]
Reactant: CCCn1c(-c2ccc(OC)cc2)c(C)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccc(OC)cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 2-(4-methoxy-phenyl)-3-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([O:25]CC)=[O:24])=[CH:4]1)[CH3:2].[OH-].[Na+].O.CO>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3cc(C)nc(C)c3)cc21
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
A mixture containing 98 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate, 50 ml of 35% aqueous sodium hydroxide solution, 500 ml of water and 100 ml of methanol was refluxed with stirring for 90 minutes and the resulting brown solution was acidified with acetic acid whereupon a light yellow precipitate separated. The mixture was allowed to stand at room temperature for about 2 hours and the precipitate was collected, washed successively with water and ethanol and then dried at 90°-95° C. to yield 86.8 g (95%) of 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid, m.p. >310° C.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:21])[CH:10]=2)=[C:5]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)[C:4]1=[O:32].[N+](C1C=C[C:39]([O:42]C(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[CH2:55]([N:57]([CH2:60][CH2:61][NH2:62])[CH2:58]C)C>C1COCC1>[CH3:31][N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:5]2[C:4](=[O:32])[N:3]([CH2:2][O:1][C:39](=[O:42])[NH:62][CH2:61][CH2:60][N:57]([CH3:58])[CH3:55])[C:7](=[O:8])[C:6]=2[C:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:21])[CH:10]=2)=[CH:23]1
Reactant: CCN(CC)CCN
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)OCN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn(C)c3cc([N+](=O)[O-])ccc23)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
1-Hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (200 mg, 0.47 mmol), prepared as in example 1a, was dissolved in THF (10 mL). The resulting red solution was cooled in an ice bath. Lithium bis(trimethylsiliyl)amide (0.56 mL, 0.56 mmol, 1 M in THF) was added dropwise to the solution to give a red suspension. After 10 min, bis(p-nitrophenyl)carbonate (200 mg, 0.66 mmol) was added. The resulting solution was stirred at 0° C. for 20 min. Diethylaminoethylamine (90 mg, 0.78 mmol) in THF (2 mL) was added. Stirring was continued for 2 hrs. The mixture was evaporated and the residue was purified by flash chromatography to give (2-dimethylamino-ethyl)-carbamic acid 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester (124 mg 46%).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH3:16])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[C:11]3=[N:12][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH3:16])[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccncc1
Reactant: Cc1nn(C2CCCCC2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1[nH]n(C2CCCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 31.7 %

Procedure:
1-Cyclohexyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (1.2 g, 5.4 mmol), 4-pyridinecarboxaldehyde (0.87 g, 8.1 mmol), toluene (125 ml) and p-toluenesulfonic acid monohydrate were combined and heated to reflux for 24 hours. The solvent was removed in vacuo and the residue was poured into water (450 ml). The obtained precipitate was collected by filtration, recrystallized from isopropanol (200 ml) and dried for 24 hours in high vacuum to afford 0.53 g (32%) of 1-cyclohexyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a cream colored solid, m.p. 292°-293° C.