Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:16]1[CH:36]=[CH:35][C:19]([O:20][C@@H:21]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>C(COC)OC.O.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>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:16]1[CH:36]=[CH:35][C:19]([O:20][C@@H:21]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccco1
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: O
Solvent: COCCOC
Product: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 120.6 %

Procedure:
0.024 mmol of tetrakis(triphenylphosphine)palladium, 12.3 mmol of 2-furanboronic acid and 7.5 ml of 2 M sodium carbonate solution are added to a solution of 6.15 mmol of ethyl (2S)-2-(4-bromophenoxy)-4-phenylbutanoate in 25 ml of dimethoxyethane. The mixture is refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate (Na2SO4) and then evaporated to dryness under vacuum. 2.6 g of a brown oil are obtained. This oil is chromatographed with a 9/1 heptane/ethyl acetate mixture as eluent. 1.5 g of an oil that crystallizes are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:13][CH2:14][N:15]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)c(O)cc1N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirring solution of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol (0.47 g, 1.88 mmol) in dichloromethane at 0° C. under nitrogen was added triethylamine (0.26 mL, 1.89 mmol), followed by methanesulfonyl chloride (0.15 mL, 1.89 mmol). The reaction mixture was stirred at 0° C. for five minutes, and then allowed to warm to room temperature. The reaction mixture was partitioned between dichloromethane and water, and the organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexanes:EtOAc 3:2) to afford 0.1 g (16% ) of 2-Isopropyl-5-(4-methanesulfonyl-piperazin-1-yl)-4-methoxy-phenol as an oil.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[S:51]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:53])=[O:52]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)S(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3=[CH:28][CH:29]=[N:30][N:23]3[CH2:22][CH2:21][C:20]=2[C:19]=1[C:31]([O:33]C)=[O:32])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3=[CH:28][CH:29]=[N:30][N:23]3[CH2:22][CH2:21][C:20]=2[C:19]=1[C:31]([OH:33])=[O:32])(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCn1nccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCn1nccc1-2
Temperature: 80 °C
Yield: 36.1 %

Procedure:
A mixture of methyl 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 20, 0.057 g) and lithium hydroxide monohydrate (0.090 g) in dioxane (4 mL) and water (1 mL) was heated to 80° C. for 32 hours. The resultant mixture was concentrated in vacuo and the residue was acidified with aqueous citric acid solution (10%) and extracted into DCM, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid (0.020 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:23]([NH:27][N:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:20](=[O:21])[N:19]([CH3:22])[C:12]2=[N:13][CH2:14]1)[CH2:24][CH2:25][CH3:26]
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CCCCN
Solvent: CN(C)C=O
Product: CCCCNN1C=c2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2=NC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 0.177 g (0.50 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 10 mL of n-butylamine and 1.0 mL of dimethylformamide was heated with stirring to reflux (110° C. oil bath). After 1 hour, solution was complete. After 20 hours reflux, the excess amine and dimethylformamide were evaporated, and the residue was triturated with water, filtered, washed with water, and dried; wt 0.180 g. Recrystallization from ethyl acetate/petroleum ether gave pure product; wt 0.116 g; mp 184°-186° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11](C2C=CC(OC)=C(OC)C=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=CC=1)C(N)=O.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[O:44][CH:45]([CH3:47])[CH3:46])[CH3:36].O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:40]2[CH:41]=[CH:42][C:43]([O:44][CH:45]([CH3:47])[CH3:46])=[C:38]([O:37][CH2:35][CH3:36])[CH:39]=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: CCOc1cc(B(O)O)ccc1OC(C)C
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Agent: NC(=O)c1cccc(N)c1
Agent: O=CC(=O)O
Solvent: O
Product: CCOc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1OC(C)C
Yield: 80 %

Procedure:
11A was prepared in a procedure similar to that of 1A using 3-aminobenzamide, 3-ethoxy-4-isopropoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 80%. 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.15 Hz, 6 H) 1.25 (t, J=7.03 Hz, 3H) 3.88-3.97 (m, 2H) 4.32-4.45 (m, 1H) 4.93 (s, 1H) 6.64-6.69 (m, 1H) 6.80 (d, J=8.35 Hz, 1H) 6.92 (dd, J=8.35, 2.20 Hz, 1H) 6.95-7.07 (m, 4H). LCMS: 373 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:12])=[N:6][C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C1(C)C=CC=CC=1.[C:20](OCC)(=[O:22])[CH3:21]>C(O)(=O)C>[CH3:12][C:5]1[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[C:4]=1[C:1]([CH2:2][C:20](=[O:22])[CH3:21])=[O:3]
Reactant: CC(=O)c1c(C)cc(C)nc1C
Reactant: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)c1c(C)cc(C)nc1C
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of 172.0 g of 3-acetyl-collidine, 4.5 l of anhydrous toluene, 195 g of ethyl acetate and 282.5 g of potassium tert.-butylate is heated at 100° for 4 hours under nitrogen. The reaction mixture is cooled and poured into 1/2 l of ice water and 140 ml of acetic acid, and the phases are separated and worked up in the customary manner to give 186.1 g of 2,4,6-trimethyl-nicotinoyl-acetone ##SPC8##
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13])=[CH:3][Cl:4].O.[NH3:17]>C(Cl)Cl>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:17])(=[O:14])=[O:13])=[CH:3][Cl:4]
Reactant: O=S(=O)(Cl)c1ccccc1OC(Cl)=CCl
Reactant: N
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reaction time: 6 h

Procedure:
A solution of 17.5 g of 2-(1,2-dichlorovinyloxy)phenylsulfonyl-chloride in 150 ml of methylenechloride is added slowly to a mixture of 30 ml of methylene chloride, 50 ml of water and 50 ml of 30% aqueous ammonia. The reaction mixture is stirred for 6 hours at a temperature of 20°-25° C. The organic phase is washed with water, dried over sodium sulfate and evaporated to a volume of 40 ml. The crystallised 2-(1,2-dichlorovinyloxy)phenylsulfonamide is separated and dried. Yield: 12.5 g, m.p. 147°-149° C.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH2:6][CH2:7][OH:8])([OH:3])=[O:2].[C:9](#[N:12])[CH2:10]O>>[C:1]([CH2:4][N:5]([CH2:6][CH2:7][OH:8])[CH2:10][C:9]#[N:12])([OH:3])=[O:2]
Reactant: O=C(O)CNCCO
Reactant: N#CCO
Product: N#CCN(CCO)CC(=O)O

Procedure:
The hydrolysis of (I) with base gives N-carboxymethylamino-2-ethanol (II). Compound (II) is then reacted with additional glycolonitrile to form N-carboxymethyl-N-cyanomethylamino-2-ethanol (III). The molar ratio of (II) to glycolonitrile is generally about 1:1. In the above reactions, hydrogen cyanide and formaldehyde can be substituted for glycolonitrile.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.I[CH3:16].O>O1CCCC1>[CH3:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)C1
Yield: 33.3 %

Procedure:
A suspension of sodium hydride (2.89 g) in tetrahydrofuran (50 ml) was stirred with cooling in an ice bath. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g) in tetrahydrofuran (50 ml) was gradually added, followed by stirring at the same temperature for 30 minutes. Then, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred with cooling in an ice bath again for 15 minutes. Iodomethane (3.09 ml) was added dropwise to the reaction mixture, followed by stirring for 2 hours. Water was gradually added to the reaction mixture. When bubbling stopped, the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1, 2:1, 1:1, then ethyl acetate). The fractions containing the target compound were concentrated to give the title compound (1.80 g, 33.3%) as a colorless oil. The fractions containing the starting material were concentrated and collected (2.10 g, 42.0%).
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:18]([F:19])=[CH:17][C:12]2[NH:13][C:14](N)=[N:15][C:11]=2[CH:10]=1.[ClH:20]>CC(C)=O.[Cu](Cl)Cl>[Cl:20][C:14]1[NH:13][C:12]2[CH:17]=[C:18]([F:19])[C:9]([F:8])=[CH:10][C:11]=2[N:15]=1
Reactant: Cl
Reactant: Nc1nc2cc(F)c(F)cc2[nH]1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC(C)=O
Product: Fc1cc2nc(Cl)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. To a mixture of copper(II) chloride (795 mg, 5.91 mmol) in acetone (20 mL) was added tert-butyl nitrite (0.53 mL, 4.43 mmol). The reaction mixture was stirred at rt for 20 minutes, 5,6-difluoro-1H-benzimidazol-2-amine (500 mg, 2.96 mmol) was then added, and the mixture was heated at reflux for 2 h (with additional portions of tert-butyl nitrite added every 0.5 h). The reaction mixture was then cooled to rt, treated with 2 N HCl, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 2-chloro-5,6-difluoro-1H-benzimidazole (580 mg, 73%), which was used without further purification in the next step. LC-MS m/z 189.2 (MH+), ret. time 1.96 min; 1H NMR (300 MHz, DMSO-d6) δ 7.62 (t, 2H), 13.5 (br s, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)cc(Cl)cc3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(Cl)cc(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) to give 1.8 g (98%) of a white solid: mp 117.0-120.0° C.; IR (diffuse reflectance) 2972, 1744, 1690, 1464, 1409, 1377, 1366, 1349, 1294, 1222, 1204, 1190, 1167, 1111, 861 cm−1; MS (EI) m/z 440 (M+), 440, 386, 385, 384, 339, 311, 310, 300, 298, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 56.97; H, 5.97; N, 6.19.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][C:51](O)=[O:52])=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:51](=[O:52])[CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([CH3:42])=[CH:44][CH:45]=2)[C:7]1=[O:12]
Reactant: Cc1ccc(CCC(=O)O)cc1
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CCC(=O)Nc2cccc3c(=O)n(CCN(C)C)ccc23)cc1
Yield: 40 %

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), 3-(4-methylphenyl)propionic acid (42 mg, 0.26 mmol) and DIPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 16 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2 gradient) gave N-[2-(2-Dimethylamino-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-3-p-tolyl-propionamide as a white solid (31 mg, 0.08 mmol, 40%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[C:6](=[O:22])[CH2:5]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[CH3:21][O:20][C:17]1[N:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH2:41][C:39]2[CH:38]=[CH:37][C:34]3[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=3[N:40]=2)[CH2:5][C:6]1=[O:22]
Reactant: COc1ccc2nccc(N3CCN(CCN)CC3=O)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)CC3=O)c2n1
Reaction time: 12 h
Yield: 37.4 %

Procedure:
To a solution of 4-(2-aminoethyl)-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone (168 mg, 0.558 mmol) in DCM-EtOH (6 mL, 5:1) at 25° C. were added Na2SO4 (158 mg, 1.11 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (108 mg, 0.558 mmol). After 12 h, Na(OAc)3BH (177 mg, 0.837 mmol) was added and following an additional 2 h, the solution was partitioned between DCM-H2O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (100 mg, 37%) as a yellow solid: LCMS (ES) m/e 480 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.81 (d, J=4.7 Hz, 1H), 8.28 (d, J=9.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.71 (d, J=4.7 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.04 (s, 3H), 3.92-3.94 (m, 2H), 3.88 (s, 2H), 3.51 (s, 2H), 3.34 (2H), 3.00-3.03 (m, 2H), 2.82-2.84 (m, 2H), 2.77-2.79 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].[H-].[Na+].[CH3:9][C:10]1[N:11]=[C:12](S(CC2C=CC=CC=2)=O)[O:13][CH:14]=1.O>CN(C)C=O>[CH2:1]([N:3]([C:12]1[O:13][CH:14]=[C:10]([CH3:9])[N:11]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: Cc1coc(S(=O)Cc2ccccc2)n1
Reactant: CCNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1nc(C)co1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-Ethyl-acetamide (1.18 g, 0.0135 m) in dry dimethylformamide (10 ml) was stirred at room temperature under nitrogen during the portionwise addition of 50% sodium hydride/oil dispersion (0.65 g, 0.0135 m). After the addition, the mixture was warmed to 50° C. and then 4-methyl-2-phenylmethylsulphinyloxazole (3.0 g, 0.0135 m) was added. The mixture was stirred at 50° C. for 5 hours and then hydrolysed with water. The solvent was evaporated in vacuo and the residue extracted with diethyl ether. Column chromatography on silica using ether gave a pale yellow oil which gave the title product as a colourless oil on distillation, b.p. 50°-51° C./0.05 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][N:28]1[C:32]([NH2:33])=[CH:31][C:30]([CH3:34])=[N:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:33][C:32]2[N:28]([CH3:27])[N:29]=[C:30]([CH3:34])[CH:31]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: Cc1cc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)n(C)n1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1,3-dimethyl-1H-pyrazol-5-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1,3-dimethyl-1H-pyrazol-5-yl)terephthalamide. MS (Q1) 480 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:20]3[CH:19]=[C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:25]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH3:85])[CH2:24]4)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Br:90])(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([Br:90])[C:20]3[CH:19]=[C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:25]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH3:85])[CH2:24]4)[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(O)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: CC(=O)Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(Br)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 386.2 %

Procedure:
9-(4-Chlorophenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenol (62.0 mg, 51.2 μmol) was dissolved in chloroform (2 mL), acetyl bromide (13 μmol, 172 μmol) was added, and the mixture was stirred at room temperature for 1 hours. After evaporation of the solvent, acetonitrile was added to the residue to allow crystallization to give 9-(4-chlorophenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-bromofluorene (63.9 mg, 50.2 μmol, 98%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:23])([F:22])[C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.OS(C(F)(F)F)(=O)=O>>[I:1][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:11]=1[C:10]([F:9])([F:22])[F:23])[NH:17][C:16](=[O:20])[C:15]2=[O:21]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1Nc2cc(C(F)(F)F)c(I)cc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.8 %

Procedure:
N-Iodosuccinimide (25.0 g, 119.5 mmol) was added to a stirred mixture of 6-trifluoromethylisatin (10.3 g, 47.8 mmol) and triflic acid (75 g) at 0° C. under nitrogen. The ice bath was removed and stirring at room temperature was continued for 7 h. The mixture was poured into ice-water and was extracted with EtOAc. The combined organic extracts were evaporated under reduced pressure and the residue was triturated with CHCl3 to produce a yellow-orange solid. Filtration of the crude solid and purification by recrystallization from CHCl3 gave 5-iodo-6-trifluoromethylisatin xxxiii (10.4 g) as an orange solid. 1H NMR (DMSO-d6) δ 7.17(s, 1 H), 8.08(s, 1 H), 11.27(s, 1 H); ms 340.0 (M−H).