Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.O1CCOCC1.[CH:30]1([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:30]1([N:33]2[CH:37]=[C:36]([C:2]3[C:3]([O:16][C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]4)[CH:35]=[N:34]2)[CH2:32][CH2:31]1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3cc(C)ccn3)c2CC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3cc(C)ccn3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and charged with 1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (111 mg, 0.30 mmol), 1,4-dioxane (15 mL), 1-cyclopropyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (139 mg, 0.59 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04 mmol), potassium carbonate (124 mg, 0.90 mmol), and water (5 mL). The resulting mixture stirred overnight at 100° C. After cooling to room temperature, the solution was diluted with ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether). The collected fractions were combined and concentrated under vacuum. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (65% to 85% acetonitrile in 7 min, flow rate 20 mL/min); Detector, UV 220&254 nm. This afforded 1-[(2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (63.6 mg, 53%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.95-1.01 (m, 4H), 1.14 (d, J=6.30 Hz, 3H), 1.30-1.45 (m, 1H), 2.10-2.30 (m, 5H), 2.34 (s, 3H), 2.55-2.70 (m, 1H), 3.55-3.65 (m, 1H), 4.68-4.85 (m, 1H), 6.75 (s, 1H), 6.85-6.95 (m, 1H), 7.20-7.32 (m, 1H), 7.55-7.58 (m, 1H), 7.72 (s, 1H), 7.89-7.93 (m, 2H). MS (ESI, pos. ion) m/z 403 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N(CCO)(CCO)CCO>C1(C)C=CC=CC=1>[CH:13]1([NH:19][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: OCCN(CCO)CCO
Product: CC(C)(C)C(=O)CC(=O)NC1CCCCC1

Procedure:
Ethylpivaloylacetate (172 g.), cyclohexylamine (99 g.), triethanolamine (1 g.) and toluene (200 ml.) are mixed in a distillation flask and heated at reflux under a 6 in. Vigreux distillation column. When the head temperature stabilized at 82° C. distillation was begun at a take off to reflux ratio of 1 to 10. Distillation was continued until a head temperature of 110° C. is obtained. The remainder of the solvent is removed in a vacuum and residue is crystallized by trituation with hexane. A yield of 201 g. of product melting at 69°-70° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH3:43])[C:21]([N:23]([CH2:33][C:34]1[C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[S:37][CH:38]=1)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH3:43])[C:21]([N:23]([CH2:33][C:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[S:37][CH:38]=2)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 112 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: C1COCC1.[Li+].[BH4-].[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:21][CH2:22][C:23](OC)=[O:24])[C:17](OC)=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[OH:18][CH2:17][C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:21][CH2:22][CH2:23][OH:24]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A 20 L reactor was charged with 10 L of dry THF and LiBH4 (400 g) and cooled to 0° C. A THF solution of (S)-dimethyl 2-(tert-butoxycarbonylamino)pentanedioate (1000 g/3.63 mol, dissolved in 2 L of dry THF) was then added dropwise while keeping the internal temp. below 15° C. The mixture was slowly warmed to room temperature and stirred for 16 h. Cooled to 0° C., then MeOH (10 L) was added dropwise to the reaction mixture to quench the excess amount of reducing reagent. Concentrated, and the residue was poured into 5 L water. After extraction with ethyl acetate, the combined organic phase was dried over Na2SO4. After filtration the solvent was removed in vacuo to give 730 g of crude (S)-tert-butyl 1,5-dihydroxypentan-2-ylcarbamate as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([C:17]=2[CH3:18])[C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=1.[CH2:20](O)[CH3:21].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([C:17]=2[CH3:18])[C:14]([O:16][CH2:20][CH3:21])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc(C)c(Oc2ccnc(Cl)c2)c1C
Yield: 67 %

Procedure:
A three necked round bottom flask containing 5-(2-chloropyridin-4-yloxy)-4,6-dimethylnicotinic acid (11.7 g, 42.0 mmol) was charged with ethanol (250 mL), benzene (300 mL) and sulphuric acid (10 mL). The flask was fitted with Dean Stark apparatus and the reaction stirred at reflux overnight. The solution was cooled and carefully neutralized with saturated NaHCO3 solution. The material was extracted with EtOAc, dried, and concentrated to afford the title compound (8.6 g, 67%) as an oil which solidified to a white solid upon standing in a refrigerator (4° C.) overnight.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.O.[OH-].[Na+]>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cn2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cn2)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
To a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.5 g, 10 mmol) in dry THF (34 mL), cooled to 0° C., was added lithiumaluminumhydride (209 mg, 2.3 mmol) portionwise. After allowing to warm up to room temperature over 1 h, the mixture was cooled to 0° C. and water (0.2 mL) was added carefully followed by aqueous sodium hydroxide (15%, 0.2 mL) and water (0.6 mL). The resulting suspension was stirred for 4 h at ambient temperature and filtered over Hyflo®. The filtrate was then concentrated and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (1.47 g, 71%) as a light yellow solid. MS: m/e=209.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[C:3]=1[NH2:21].[N:22]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:21]=[N:22][N:9]([CH2:10][C:11]3[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=N[O-]
Reactant: COc1cc(CNc2nc(N)nc(Cl)c2N)cc(OC)c1
Agent: [Na+]
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1

Procedure:
A solution of 6-chloro-N4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 6.185 min. 1HNMR (CDCl3): δ 6.54–6.53 (d, 2H), 6.41–6.40 (d, 1H), 5.58 (s, 2H), 5.54 (s, 2H), 3.78 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[N:27]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=O)[CH2:29][CH2:28]1.[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>O1CCCC1.O>[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:20]3[C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)[CH2:32][CH2:31]2)=[O:35])=[CH:39][CH:38]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)C1CCN(c2ccnc3ccc(Br)cc23)CC1

Procedure:
0.34 mL triethylamine and 0.13 mL isobutyl chloroformate were added to a solution of 50 mg 1-(6-bromo-4-quinolyl)-4-piperidinecarboxylic acid in tetrahydrofuran (5 mL) with stirring under ice-cooling, and the mixture was stirred for 0.5 hour in a stream of nitrogen. To this solution was added a solution of 1.5 mL 4-fluoroaniline in tetrahydrofuran (8 mL), and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 73 mg of the title compound as pale purple crystals.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH:44]([S:47](Cl)(=[O:49])=[O:48])([CH3:46])[CH3:45]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([S:47]([CH:44]([CH3:46])[CH3:45])(=[O:49])=[O:48])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(S(=O)(=O)C(C)C)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in CH2Cl2 (1.3 mL) was added 3 mL of saturated sodium bicarbonate followed by isopropylsulfonyl chloride (0.1 mL, 0.9 mmol). The reaction mixture was stirred overnight, taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica chromatography (silica pre-washed with methanol) eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-(isopropylsulfonyl)-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide (0.12 g, 66%) as a colorless solid. MS: 647.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:28]([CH3:42])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([CH3:42])=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 85.1.1) to give the title compound as a white solid. (HPLC: tR 2.22 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.17 (m, 1H), 8.13-8.09 (m, 2H), 8.02-7.98 (m, 1H), 7.61-7.59 (m, 1H), 7.30-7.28 (m, 1H), 4.20-4.12 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 2.39 (s, 3H), 1.97 (s, 3H), 1.43 (t, 3H))
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[C:18]([O:19][C:20]3[C:25]=1[CH:24]=[CH:23][C:22](=[NH:26])[C:21]=3[Br:27])=[C:17]([Br:28])[C:16]([NH2:29])=[CH:15][CH:14]=2)C.Cl.C(OC(=O)C1C=CC=CC=1C1C2C(OC3C=1C=CC(=N)C=3Br)=C(Br)C(N)=CC=2)CCCCCCC.Cl.C(OC(=O)C1C=CC=CC=1C1C2C(OC3C=1C=CC(=N)C=3Br)=C(Br)C(N)=CC=2)CCC.Cl.C(OC(=O)C1C=CC=CC=1C1C2C(OC3C=1C(=N)C(N)C(CC)C=3)=CC(CC)=CC=2)CCC>>[ClH:1].[CH3:2][O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[C:18]([O:19][C:20]3[C:25]=1[CH:24]=[CH:23][C:22](=[NH:26])[C:21]=3[Br:27])=[C:17]([Br:28])[C:16]([NH2:29])=[CH:15][CH:14]=2
Reactant: CCOC(=O)c1ccccc1-c1c2ccc(=N)c(Br)c-2oc2c(Br)c(N)ccc12
Agent: CCCCCCCCOC(=O)c1ccccc1-c1c2ccc(=N)c(Br)c-2oc2c(Br)c(N)ccc12
Agent: CCCCOC(=O)c1ccccc1-c1c2ccc(=N)c(Br)c-2oc2c(Br)c(N)ccc12
Agent: CCCCOC(=O)c1ccccc1C1=C2C(=N)C(N)C(CC)C=C2Oc2cc(CC)ccc21
Product: COC(=O)c1ccccc1-c1c2ccc(=N)c(Br)c-2oc2c(Br)c(N)ccc12

Procedure:
2-(4, 5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)-benzoic acid ethyl ester hydrochloride; 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)-benzoic acid octyl ester hydrochloride; 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)-benzoic acid n-butyl ester hydrochloride; 2-(6-ethyl amino-3-ethyl imino-3H-xanthen-9-yl)-benzoic acid n-butyl ester hydrochloride; and photoactivable derivatives thereof. These derivatives are utilized in an amount to achieve appropriate intracellular levels of the derivative when irradiation of a suitable wavelength and intensity is applied to photoactivate the derivative and thereby induce cell killing.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]([CH2:12][N:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:16]4=[N:23][NH:24][C:25](=[O:26])[C:15]4=[N:14]3)=[CH:8][CH:7]=2)[N:3]=[CH:2]1.I[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1[CH3:35].CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.[Cu]I>[CH3:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=1[N:24]1[C:25](=[O:26])[C:15]2=[N:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[CH:7][CH:8]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]2=[N:23]1
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-c4cscn4)nc3)nc1-2
Reactant: Cc1cccc(I)c1C
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nc3c4ccccc4n(Cc4ccc(-c5cscn5)nc4)nc-3c2=O)c1C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-{[6-(1,3-Thiazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (66 mg, 0.18 mmol) was dissolved in degassed N,N-dimethylformamide (1 mL) and copper (I) iodide (35 mg, 0.22 mmol, 1.2 equiv), 1-iodo-2,3-dimethylbenzene (51 mg, 0.22 mmol, 1.2 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (78 mg, 0.549 mmol, 3 equiv) and potassium phosphate (0.27 g, 1.3 mmol, 7 equiv) were added. The vessel was sealed and placed into an oil bath preheated at 105° C. for 40 minutes. The mixture cooled to ambient temperature, diluted with water (5 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed three times with water and once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.87 (1H, s), 8.69 (1H, s), 8.31 (1H, d, J=8.2 Hz), 8.16 (2H, m), 7.77 (1H, d, J=8.2 Hz), 7.57 (4H, m), 7.28 (1H, m), 7.22 (1H, d, J=3.9 Hz), 5.90 (2H, s), 2.37 (3H, s), 2.21 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 465.1499 [(M+H)+; calculated for C26H21N6OS: 465.1492].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:26])[NH:18][C:17]([CH3:27])=[C:16]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:26])[NH:18][C:17]([CH3:27])=[C:16]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1O
Reaction time: 7 h
Yield: 32.8 %

Procedure:
Diethyl 1,4-dihydro-4-(2-benzyloxyphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (13.3 grams, 0.03 mole) was dissolved in 250 ml ethanol, 1.5 grams of 10% palladium on carbon was added and the reaction mixture reduced on a Parr Hydrogenator. A drop of 111 psi was noted over a period of seven hours. The Pd-C was filtered off, the solvent removed from the filtrate. Two recrystallizations from acetonitrile yielded 3.4 grams (34%) of the desired product, m.p. 159°-161° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.CO[C:12](OC)(OC)[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[NH:8][C:12]([CH2:13][CH2:14][CH3:15])=[N:1]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1nc2ncnc(Cl)c2[nH]1

Procedure:
To a solution of 4,5-diamino-6-chloropyrimidine (0.289 g, 2 mmol) in 2-methoxyethanol (10 ml) were added trimethylorthobutyrate (0.5 ml, 3 mmol) and p-toluenesulfonic acid (0.03 g), and the mixture was refluxed for 18 hours and then concentrated in vacuo. The residue was partitioned between water and and ethylacetate. The organic phase was then washed with brine and dried (MgSO4). The crude product obtained after evaporation of the solvent was purified by flash column chromatography on silica-gel using ethylacetate/hexane (1:1). The fractions containing pure product were pooled and concentrated in vacuo, and then allowed to stand at room temperature overnight. The crystalline product was filtered and dried.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10](O)[CH3:11])[CH:6]=[CH:7][C:8]=1[Cl:9]>CC(O)=O>[Br:1][CH:10]([C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=1)[CH3:11]
Reactant: CC(O)c1ccc(Cl)c(Cl)c1
Reactant: Br
Solvent: CC(=O)O
Product: CC(Br)c1ccc(Cl)c(Cl)c1

Procedure:
This compound is prepared by the procedure described in Preparation 3.4 from 25 ml of a 33% solution of HBr in AcOH and 5 g of 3,4-dichloro-1-(1-hydroxyethyl)benzene. 6.4 g of the expected product are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[OH:42][C:35]1[C:34]([CH2:33][NH:32][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])=[CH:14][CH:13]=2)=[C:39]([CH3:40])[CH:38]=[C:37]([CH3:41])[N:36]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(CCO)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A mixture of 4-(4-hydroxybutan-2-yl)benzoic acid (290 mg, 1.5 mmol), 1-ethyl-3-(3-dimethyllamino propyl)carbodiimide hydrochloride (432 mg, 2.25 mmol), N-hydroxybenzotriazole (3.4 mg, 2.25 mmol) and triethylamine (455 mg, 4.5 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (228 mg, 1.5 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloro methane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (41 mg, 8.3%). LRMS (M+H+) m/z: calcd 328.18 found 328; 1H. NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.11 (s, 1H), 4.49 (s, 2H), 3.44-3.42 (m, 2H), 2.94 (q, J=7.2 Hz, 1H), 2.36 (s, 3H), 2.42 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.26 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:36]([O-])=O)=[C:7]([OH:35])[C:8]([NH:12][C:13](=[O:34])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([CH3:26])[CH3:25])=[CH:20][C:19]=2[C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])[CH2:15][CH3:16])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[OH-].[Na+].O.[C:42](O)(=[O:44])C>CO>[Cl:11][C:10]1[C:5]2=[N:4][C:1](=[O:3])[CH2:2][C:42](=[O:44])[N:36]=[C:6]2[C:7]([OH:35])=[C:8]([NH:12][C:13](=[O:34])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([CH3:25])[CH3:26])=[CH:20][C:19]=2[C:29]([CH2:32][CH3:33])([CH3:30])[CH3:31])[CH2:15][CH3:16])[CH:9]=1
Reactant: CC(=O)O
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2
Temperature: 25 °C

Procedure:
In 200 ml of methanol was dispersed 40 g of the 3-acetylamino-4-chloro-2-nitro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol, and the dispersion was stirred while refluxing for 5 hours together with 9 g of sodium hydroxide and 40 ml of water. The reaction mixture was cooled to room temperature and then poured into 300 ml of water. Upon dropwise addition of 15 ml of acetic acid, red crystals were precipitated. The crystals were collected by filtration, recrystallized from acetonitrile, and dried to provide 21 g of the desired compound.