Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.Cl[Sn](Cl)(Cl)Cl.[CH2:22]=[O:23]>C1(C)C=CC=CC=1>[OH:23][C:22]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: C=O
Reactant: Cc1ccccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(C=O)c1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
o-Cresol 20.0 g (185 mmol) was dissolved in toluene 400 ml and thereto was added 2,6-lutidine 18.4 g (171 mmol). SnCl4 4.8 g (18 mmol) was added to the mixture and the mixture was stirred for 30 min. at 20° C. Thereto was added paraformaldehyde (purity: 95 weight %) 12.9 g (409 mmol) and the mixture was stirred at 80° C. for 5 hours to the conversion of 78%. And the reaction was kept for 10 hours at 100° C. to confirm the disappearance of the raw material, o-cresol. The reaction solution was cooled to room temperature, extracted with water-toluene in a separatory funnel and the organic layer was dried over anhydrous magnesium sulfate and dried in vacuo to give 2-hydroxy-3-methylbenzaldehyde 24.9 g (yield: 99%, selectivity: 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](I)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:38]=[C:37]([CH3:39])[C:36]([CH3:40])=[C:35]1[CH:41]([OH:44])[C:42]#[CH:43])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(N(CC)CC)C.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:43]#[C:42][CH:41]([C:35]3[N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH:38]=[C:37]([CH3:39])[C:36]=3[CH3:40])[OH:44])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1cc2c(I)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: C#CC(O)c1c(C)c(C)cn1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cn(C(=O)OC(C)(C)C)c(C(O)C#Cc2c(F)ccc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-tert-butoxycarbonyloxy-5-fluoro-4-iodo-indole-1-carboxylic acid tert-butyl ester (from Example 2 above) (1 g, 2.22 mmol), and 3,4-dimethyl-2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester (from Example 45 above) (1.38 g, 5.54 mmol) in dry THF(12 mL) and triethylamine(Aldrich, 12 mL) was degassed by bubbling argon through the solution for 10 minutes. At this time copper(I) iodide (Aldrich, 84.4 mg, 0.44 mmol) and (Ph3P)4Pd (0.25 g, 0.22 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. Flash chromatography (silica gel, 85:15 hexanes/ethyl acetate) afforded 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester as an orange oil. (Yield 0.76 g, 57%).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])=[CH:25][C:24]=3[F:36])[CH:14]=2)=[CH:9][CH:8]=1.CC(O)=O.O>O>[CH:33]1([NH:32][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:10]5[CH:11]=[N:12][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=5)[S:21][C:20]=34)=[C:24]([F:36])[CH:25]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)nc4)sc23)c(F)c1)NC1CC1
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 281 (2.71 mg, 5.35 mmol) in a mixture AcOH/water (32 mL/8 mL) was heated at 90° C. for 29 h. After cooling to RT the reaction mixture was diluted with water to form a precipitate that was collected by filtration and dried under vacuum to afford the title compound 282 (2.25 g, 5.02 mmol, 94% yield) as a brown solid. MS (m/z): 449.2 (M+H).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][NH2:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]([O:36]C(=O)C(F)(F)F)=[O:35]>C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][NH:29][O:36][C:34](=[O:35])[C:33]([F:44])([F:43])[F:32])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CN)n2Cc2ccccc2)n(C)c1=O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CNOC(=O)C(F)(F)F)n2Cc2ccccc2)n(C)c1=O
Reaction time: 3 h
Yield: 95 %

Procedure:
A stirring solution of (R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-benzyl-3-methylxanthine in chloroform (30 ml) was treated with trifluoroacetic anhydride (1.0 g, 4.76 mmol) and stirred for 3 hours. Concentration under reduced pressure gave a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methyl 8-(N-(trifluoroacetoxy)aminomethyl)xanthine (1.0 g, 95% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12
Reactant: C[O-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Na (370 mg, 16.12 mmol) was dissolved in MeOH (5 mL) and 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.61 mmol) was added to the sodium methoxide solution. The reaction mixture was stirred for 8 hours for 60° C. The reaction mixture was quenched with water and the organic solvent was removed under reduced pressure. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent to afford title compound (380 mg, 77% yield). 1H NMR (600 MHz, CDCl3) δ 10.51 (s, 1H), 8.74 (s, 1H), 7.36 (d, J=3.6 Hz, 1H), 6.90 (d, J=4.2 Hz, 1H), 5.72 (s, 2H), 4.48 (s, 3H), 3.60 (t, J=7.8 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 307 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[CH:16](O)=[O:17].O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]([CH:16]=[O:17])[CH2:6][C:7]1[CH:8]=[C:9]([F:14])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: COC(=O)CNCc1cc(F)cc(F)c1
Reactant: O=CO
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)CN(C=O)Cc1cc(F)cc(F)c1
Yield: 99.3 %

Procedure:
A solution of N-(3,5-difluorobenzyl)-glycine methyl ester (7.61 g, 0.0352 mole) and formic acid (1.33 ml, 0.0352 mole) was heated at reflux in xylene (60 ml) with azeotroic removal of water for 2.5 hours and the solvent was removed under vacuum to give the product as an oil (8.50 g, 99%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[C:36]1([C:5]2[C:6]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[NH:29][C:28]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=6)=[N:27][N:26]=5)[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[N:7][C:8]3[C:3]([CH:4]=2)=[C:2]([NH:42][NH2:43])[N:11]=[CH:10][CH:9]=3)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NN
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A suspension of 8-8 (4.3 g, 7.7 mmol) in 30 mL 1,4-dioxane and hydrazine (7.4 g, 231.1 mmol) was heated in a microwave reactor at 100° C. for 5 mins. The mixture was cooled and concentrated to remove solvents. Toluene 40 mL (×3) was added and removed under vacuum to remove the residual hydrazine. The desired product 8-9 was obtained as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[SH-:17].[Na+]>O>[CH2:15]([O:14][C:12]([C:4]1[CH:3]=[C:2]([SH:17])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)=[O:13])[CH3:16]
Reactant: [SH-]
Reactant: CCOC(=O)c1cc(Cl)n2nc(C)nc2n1
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2nc(C)nc2n1
Yield: 74.1 %

Procedure:
The product obtained in Step 2 (15 g) was added all at once at room temperature to a solution of sodium hydrosulfide (15 g) in 300 ml of water with stirring under a nitrogen stream, and the reaction mixture was worked up in the same manner as Step 3 of Example 37, affording 11 g of the objective compound as yellow crystals.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: Br[Mg]c1cccs1
Reactant: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Solvent: C1CCOC1
Product: OC(c1cccc(OCCCCCCCCC2OCCO2)c1)c1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde (1.0 g, 3.25 mmol) in THF (30 mL) at −78° C. under an atmosphere of nitrogen, a solution of 2-thienylmagnesium bromide (1M in THF, 4.23 mL, 4.23 mmol) was added over 10 minutes. After stirring at −78° C. for 1 hour, the reaction was allowed to warm to RT and stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in iso-hexane to afford the title compound (1.12 g, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.C([O:19][B:20]([O-])[O-:21])CCC>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:21])[OH:19])=[CH:3][CH:4]=1
Reactant: CCCCOB([O-])[O-]
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of 4-bromoanisole (100 g, 0.53 mol) in dry THF (1 L), BuLi (494 ml-, 0.64 mol) was added slowly at −78° C. and stirred for 2 h. To this was added n-butylborate (147 g, 0.64 mol) slowly over 30 min and stirred at RT for 12 h. After completion, the reaction mixture was quenched with water (400 ml), acidified with 1.5N HCl and filtered off the solid precipitate. The solid was washed with water and dried to give 4-methoxyphenylboronic acid (75 g, 92%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[CH3:22]>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH2:21][CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3]
Reactant: CCc1ccccc1N
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1CC
Temperature: 65 °C
Reaction time: 4 h
Yield: 29.8 %

Procedure:
A mixture of 3-propanoyl-4-chloro-8-(2-methylthioethoxy)quinoline (0.093 g, 0.34 mmol) and 2-ethyl aniline (0.048 g, 0.39 mmol) in acetonitrile (1 ml) was heated to 65° C. and stirred 4.0 h. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed (SiO2 ; ethyl acetate) yielding 40 mg (30%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[H-].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>COCCOC>[CH2:19]([O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Nc1ccccc1OC(F)(F)F
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000 mL) and cooled to −5° C. Sodium hydride (12.3 g, 55%, 0.282 mol) was added in portions and the suspension was allowed to warm to room temperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop by drop and the mixture was stirred for 2 h at room temperature and for 1.5 h at reflux after addition was complete. Hydrolysis was with water (110 mL). The phases were separated and the water phase was extracted with ethyl acetate. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 70.6 g of brown oil, which was purified by chromatography on silica gel with hexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g, 62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M+)).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:21]>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:2](=[S:21])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2cc3ccccc3nc2Cl)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Fc1ccc(-c2cc3ccccc3[nH]c2=S)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-3-(p-fluorophenyl)quinoline (6.03 g., see Example 3) and thiourea (1.8 g.) in ethanol (30 ml.) was heated under reflux for 2 hr. The solution was allowed to cool to ambient temperature, the solid which precipitated was filtered off, dispersed in 1 M-sodium hydroxide solution (100 ml.), and the dispersion heated on a steam bath for 20 min. The mixture was acidified with 2 M-hydrochloric acid solution. The resulting mixture was filtered, the solid residue was stirred with hot ethanol (75 ml.) for 5 min., and then filtered. There was thus obtained as the solid residue 3-(p-fluorophenyl)quinolin-2-thione, m.p. 259°-262°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:27]1([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:33][C:34](=[O:35])[C:36]2[CH:37]=[CH:38][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:42][CH:43]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 213 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C31H27N5O2: 502.23; found: 502.03.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[I:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]([NH:14][NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:8]([I:7])[CH:9]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NN)cc1I
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NNC(=O)C2CC2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of cyclopropanecarbonyl chloride (1.81 mL, 20.0 mmol) in dichloromethane (20 mL) was added dropwise to a stirred solution of 3-iodo-4-methylbenzohydrazide (preparation 55b, 5.00 g, 18.1 mmol) and triethylamine (2.78 mL, 20.0 mmol) in dichloromethane (80 mL) at 0° C. After 2 hours stirring at ambient temperature, the mixture was concentrated in vacuo and water was added to the residue. The resultant precipitate was filtered and was washed with water and diethyl ether to give the title compound (4.75 g, 76%) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH3:15])(=[O:13])=[O:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(I)c2occc2c1
Reactant: Cc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1NS(=O)(=O)c1cc(I)c2occc2c1
Reaction time: 8 h

Procedure:
7-Iodo-1-benzofuran-5-sulfonyl chloride (10 g, 29.2 mmol; Intermediate 56) and 2-methyl aniline (3.43 mL, 32.1 mmol) were dissolved in dichloromethane (150 mL) and pyridine (3.53 mL, 43.8 mmol) was added. The solution was stirred overnight and washed with 1 M HCl (2×100 mL), dried over sodium sulfate and evaporated to give the crude solid product that was recrystallized from methanol. Yield: 5.32 g (44%) of a beige solid.
Reaction SMILES: C([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])(C)C.C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[C:44](Cl)=[O:45]>ClCCl>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[C:44]([NH:29][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([OH:28])=[C:17]([N:18]=[N:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:8]([S:5]([OH:4])(=[O:7])=[O:6])=[CH:9]2)=[CH:14][CH:13]=1)=[O:45]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N=Nc2c(S(=O)(=O)O)cc3cc(NC(=O)c4ccc(OC)c(OC)c4)ccc3c2O)cc1
Reaction time: 16 h

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo-napthalene-2-sulfonic acid isopropyl ester (Example 6, 100 mg, 0.24 mmol ) was dissolved in dichloromethane (15 mL) and diisopropylethylamine (84 μL, 62 mg, 0.48 mmol). 3,4-Dimethoxybenzoyl chloride (56 mg, 0.28 mmol) was added under nitrogen and the reaction mixture was allowed to stir for 16 h. The solution was washed with water, 1N HCl, and saturated sodium bicarbonate solution. The organic layer was dried with MgSO4 and concentrated. This concentrate was purified by chromatography (silica gel, eluent: 50% ethyl acetate/hexane) to provide the sulfonic acid, isopropyl ester (27 mg, 0.047 mmole, 17%). This ester (16 mg, 0.028 mmole) was suspended in 2-butanone (0.5 mL) and sodium iodide (6 mg, 0.041 mmole) was added. The resulting suspension was heated with stirring to 60° C. for 72 h. The solvent was removed under a stream of nitrogen. The remaining solid was suspended in acetone and filtered to provide the title compound (9 mg, 0.016 mmole, 67%, calculated from the isopropyl ester) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 10.39 (s, 1H), 8.26 (d, J=9 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 2H), 7.68 (d, J=9 Hz, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.10 (m, 3H), 3.95 (m, 9H): Analytical HPLC: 82% pure: MS (ES-NEG): [M−H] 536.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14]>CC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-26A: To a solution of 4-acetyl-benzenesulfonyl chloride (Hoffman, R. V. Org. Syn. VII, 508; 4.18 g, 19.1 mmol) in acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min. The precipitate was filtered and the residue was washed with water and dried in vacuo to afford 4-acetyl-benzenesulfonamide as a white solid (3.54 g, 93%). 1H NMR (DMSO-d6) δ 8.10 (d, J=9 Hz, 2H), 8.03 (d, J=9 Hz, 2H), 4.86 (bs, 2H), 2.65 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=O)C.[CH3:38][NH2:39]>CO>[CH3:38][NH:39][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0.010 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.56 (br. S, 1H), 9.33 (s, 1H), 8.77 (s, 1H), 7.51 (dd, 1H, J=2.3 Hz, J=9.31 Hz), 7.34 (d, 1H, J=7.9 Hz), 7.11 (dd, 1H, J=1.7 Hz, J=7.8 Hz), 6.99 (br. S, 1H), 2.86-3.05 (m, 13H), 2.12-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H26N6O3: 482.21, Found: 483.2 (M+H).