Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:14]([O:16]C(C)(C)C)=[O:15])[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)OC(C)(C)C)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2[nH]c(C(=O)O)cc12

Procedure:
To a solution of 3.8 g 1H-Indole-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester were dissolved in 100 ml TFA. After 1 h at RT 150 ml toluene were added and the solvents were removed under reduced pressure. The residue was lyophilised after addition of water and acetonitrile. Yield: 2 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 73.6 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (200 mg) and 4-piperidinecarboxylic acid, ethyl ester (280 mg). Purification (SiO2, ethyl acetate:isohexane 25:75 as eluant) gave the sub-title compound as an oil (200 mg).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:8]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:9]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of benzyl cyanide (11.7 g, 100 mmol) in anhydrous THF (100 mL) was added slowly the solution of LiHMDS in THF (1 M, 200 mL, 200 mmol) at −78° C. in a dry-ice/acetone bath. After addition, the mixture was warmed to rt, stirred for 1 h, cooled to −78° C., and added ethyl bromoacetate (32.9 g, 198 mmol) dropwise. After addition, the reaction mixture was stirred at rt overnight. When TLC showed that the benzyl cyanaide was consumed, the reaction mixture was quenched with satd aq NH4Cl (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with satd aq NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated to give the crude final product, which was purified by chromatography on a silica gel column eluted with PE/EtOAc=50:1-10:1 to give diethyl 3-cyano-3-phenylpentanedioate (10.6 g, yield 37%) as brown oil. 1H NMR (CDCl3 400 MHz): δ 7.45 (d, 2H), 7.37 (t, 2H), 7.28 (t, 1H), 4.06 (q, 4H), 3.2 (m, 4H), 1.12 (t, 6H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:39]1[CH:40]=[N:41][C:42]([N:45]2[C:49]([CH3:50])=[CH:48][CH:47]=[C:46]2[CH3:51])=[CH:43][CH:44]=1)[CH2:10][N:11]([CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[O:21]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:53]1[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd]>[C:14]([O:13][C:12]([N:11]([CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:53]3[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=3)[CH:26]=2)[O:21]1)[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:39]1[CH:40]=[N:41][C:42]([N:45]2[C:49]([CH3:50])=[CH:48][CH:47]=[C:46]2[CH3:51])=[CH:43][CH:44]=1)=[O:18])([CH3:16])([CH3:15])[CH3:17]
Reactant: Cc1ccc(C)n1-c1ccc([C@H](CN(C[C@H]2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)cn1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(-n4c(C)ccc4C)nc2)C(=O)OC(C)(C)C)O3)cc1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
Argon was bubbled through a solution of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 370, 395 mg, 0.55 mmol) in toluene (15 mL) and 1,4-dioxane (3 mL) for 10 minutes. Bis(diphenylphosphino)ferrocene-palladium (40 mg) and methyl 4-iodobenzoate (216 mg, 0.83 mmol) were added, and bubbling with argon was continued for another 5 minutes. 2 N aq. sodium carbonate solution (3 mL, 6 mmol) was added and the reaction mixture was heated (85° C.) for 16 hours. After cooling, the mixture was filtered through a pad of silica gel and Celite® using ethyl acetate to rinse. The filtrate was concentrated in vacuo and then flash chromatography of the residue over silica gel using 20% ethyl acetate/hexanes afforded 276 mg (69%) of the desired product. The product had: 1H NMR (CDCl3, δ): 8.65 (d, J=20.0 Hz, 1 H), 8.13 (d, J=7.9 Hz, 2 H), 7.91 (dd, J=16.8, 8.1 Hz, 1 H), 7.67 (d, J=7.6 Hz, 2 H), 7.24-7.47 (m, 3 H), 6.93 (dd, J=8.1, 1.8 Hz, 1 H), 5.98 (d, J=3.9 Hz, 1 H), 5.23 (dd, J=43.5, 5.5 Hz, 1 H), 4.21-4.43 (m, 1 H), 4.00 (s, 3 H), 3.37-3.95 (m, 4 H), 2.84-3.09 (m, 2 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.03-2.18 (m, 1 H), 1.74-1.91 (m, 1 H), 1.59 (d, J=10.4 Hz, 9 H), 0.99 (s, 9 H), 0.17 (s, 3 H), 0.00 (s, 3 H); mass spectroscopy gave m/z=726.4 [M+H]+ (calc'd exact mass for C42H55N3O6Si=725.4).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Na+].Cl[C:27]([F:32])([F:31])C([O-])=O>CN(C=O)C.O>[F:31][CH:27]([F:32])[O:18][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]([OH:17])[CH:14]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
To a solution of 2-[[(2,3-difluorophenyl)methyl]thio]-4,6-pyrimidinediol (3 g) in DMF (30 mL), cesium carbonate (4.3 g) and chlorodifluoro-acetic acid sodium salt (1.9 g) was added. The resulting mixture was heated at 100° C. for 2 h. The reaction mixture was cooled then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a white solid. Yield: 0.4 g
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Br[CH2:16][CH2:17][CH2:18][O:19][CH3:20]>>[CH3:20][O:19][CH2:18][CH2:17][CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: COCCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 1-bromo-3-methoxypropane according to Method AC (90° C.) and was isolated as an orange gum (quantitative) that was used without further purification. LCMS (ES+) 267.0 (M+H)+, RT 2.96 minutes (Method 1).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[CH3:21][C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[CH:24][CH:23]=1>C(#N)C>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of potassium ethyl malonate (1.62 g, 9.51 mmol, 2.1 eq) in acetonitrile (14 mL) at 10° C. under nitrogen was added triethylamine (1.8 mL) followed by MgCl2 (1.1 g, 11.3 mmol, 2.5 eq). The mixture was allowed to stir at room temperature for 2.5 hours. The mixture was cooled to 0° C. and 4-methylbenzoyl chloride (700 mg, 4.53 mmol, 1 eq) was added dropwise over 15 minutes followed by addition of triethylamine (0.3 mL). The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and cooled to 10° C. The solution was washed (cautiously) with 4N aqueous HCl. The aqueous layer was back extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in aqueous 2N NaOH and extracted 3× with diethyl ether. The ether extracts were combined, washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated. The title compound was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1>ClCCl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:31](=[O:37])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
In dichloromethane (30 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.55 g), followed by the addition of succinic anhydride (1.50 g). The mixture was stirred at room temperature for 2 hours. The dichloromethane was distilled off and, following the addition of 3% aqueous phosphoric acid solution (100 ml), the residue was extracted with ethyl acetate (150 ml). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride (100 ml×2), dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was treated with ether and the resultant powder was recovered by filtration, washed with ether and dried under reduced pressure over phosphorus pentoxide. The procedure provided 7β-(2-thienylacetamido)-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (4.00 g).
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH2:2][CH3:3].[C:6]1([CH:12]=[C:13]2[C:18](=O)[C:17](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][S:15](=[O:27])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[C:6]1([CH:12]2[N:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:18]3[C:17](=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][S:15](=[O:27])[CH2:14][CH:13]23)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)CS(=O)CC1=Cc1ccccc1
Reactant: CCCNN
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3)CS(=O)CC2C1c1ccccc1
Yield: 22.3 %

Procedure:
n-Propyl hydrazine (1.14g) is added to a suspension of 3.8g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1-oxide in 75ml of methanol and the mixture is heated at reflux temperature for 2 hours. The crystals which form on cooling are collected to give 1.0g of the title compound, melting point 176°-177.5°C. The mother liquor is concentrated in vacuo and the residue is crystallized from acetonitrile/water (2:1) to yield an additional 0.6g of the title compound, melting point 176.5°-178°C. (isomer A)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([NH:9][C@H:10]([C:12]2[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14](=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH3:11])=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.CN(C)C1C=CN=CC=1>[C:37]([NH:1][C:2]1[S:3][C:4]([C:7]([NH:9][C@H:10]([C:12]2[N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14](=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH3:11])=[O:8])=[CH:5][N:6]=1)(=[O:39])[CH3:38]
Reactant: C[C@H](NC(=O)c1cnc(N)s1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(C(=O)N[C@@H](C)c2cc3cccc(Cl)c3c(=O)n2-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-amino-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide (2) (100 mg, 0.24 mmol) and triethylamine (0.07 mL, 0.48 mmol) in anhydrous THF (5 mL), acetyl chloride (0.025 mL, 0.35 mmol) and 4-(dimethylamino)pyridine (2.5 mg, 0.02 mmol) were added and the resulting mixture was stirred at RT for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-2-acetamido-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)thiazole-5-carboxamide (compound 50). ESI-MS m/z: 467.0 [M+H]+.
Reaction SMILES: C(OC1C=CC(C[C:14]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=CC=1)C1C=CC=CC=1>[Pd]>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:14]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccc(C(C)C)cc1)C(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C(Oc1ccc(C(C)C)cc1)(C(=O)OCC)c1ccc(O)cc1
Yield: 198.1 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using diethyl 2-(4-benzyloxybenzyl)-2-(4-isopropylphenoxy)malonate (32.3 g), which is the product of Reference example 5(b), and palladium on carbon (5%, 2.00 g) and the reaction mixture was treated to afford the desired compound (25.2 g) as a syrup.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>ClC1C=CC=CC=1Cl>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[NH:19][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Solvent: Clc1ccccc1Cl
Product: O=C1c2cccc(NCCc3ccc(O)cc3)c2C(=O)c2c(NCCc3ccc(O)cc3)cccc21
Temperature: 160 °C
Yield: 60.6 %

Procedure:
A mixture of 27.7 grams (0.1 mole) of 1,8-dichloroanthraquinone, 30 grams (0.22 mole) of p-(2-aminoethyl)phenol in 200 milliliters of o-dichlorobenzene was heated to 160° C. for 18 hours. The mixture was cooled to room temperature, and the product was collected by filtration. It was recrystallized from isopropanol to yield 29 grams (62%) of 1,8-bis[2-(p-hydroxyphenyl)ethylamino]anthraquinone as a red powder, m.p. 181°-182° C., vis (DMF), λmax 520 nm (ε12,000); ms 478 (M+); Calcd. for C30H26N2O4 : C, 75.29; H, 5.48; N, 5.86; O, 13.38; Found: C, 74.94; H, 5.30; N, 5.63; O, 13.17.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[C:12]1([CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:25](/[S:22]([NH:21][CH2:20][CH2:19][CH2:18][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:24])=[O:23])\[C:26]#[N:27])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: Cc1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C)c1O

Procedure:
The titled compound was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanomethylsulfonamide under the similar conditions as described for EXAMPLE 12 (part B).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 1 h

Procedure:
To a solution of benzyl trans-4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylate (52.4 g, 0.172 mol) in MeOH (500 mL) was added 10% Pd/C (5 g). The reaction was hydrogenated at 40 psi for 1 hour and then the catalyst was removed by filtration. The filtrate was concentrated to afford trans-4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid. 1H NMR (CDCl3, 500 MHz) δ 4.12 (q, J=7.1 Hz, 2H), 2.24 (m, 1H), 2.19 (d, J=7.1 Hz, 2H), 1.98-2.04 (m, 2H), 1.81-1.87 (m, 2H), 1.77 (m, 1H), 1.46 (qd, J=13.0, 3.4 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H), 1.02 (qd, J=13.0, 3.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:15])([O:12]CC)[O:9]CC)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([P:8](=[O:9])([OH:15])[OH:12])=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Agent: Cl
Product: O=P(O)(O)c1ccc(F)cc1

Procedure:
Diethyl 4-fluorophenylphosphonate (600 mg, 2.55 mmol) was combined with 8M HCl (10 mL, excess) and the mixture refluxed overnight. The reaction was cooled and filtered to remove dark specks. The solvent was removed under vacuum until a solid began to form. The mixture was then put in the refrigerator for several hours. The solid was dried to yield an off-white powder (P80 mg). 1H NMR (400.14 MHz, DMSO) δ 7.71 (ddd, J=12.49, 8.52, 5.99 Hz, 2H), 7.28 (ddd, J=9.02, 9.02, 2.65 Hz, 2H). 31P{1H} NMR (161.97 MHz, DMSO): δ 12.81. Analysis calculated (found) %: C 40.93 (40.33), H 3.43 (3.49).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]4)[N:18]=3)[N:15]=2)[N:10]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)CO>[NH:33]1[CH2:34][CH:31]([CH2:30][N:19]2[C:20]3[C:25](=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:9][N:10]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:32]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: OCC(F)(F)F
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CNC4)c4ccc(OC(F)F)cc34)nc12

Procedure:
A stirred solution of tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (180 mg, 257 μmol) in 2,2,2-trifluoroethanol (2 mL) was heated in a microwave at 150° C. for 6 h then cooled, concentrated and used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[CH3:11][S:12]([O:7][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][S:12]([CH3:11])(=[O:14])=[O:13])[CH:3]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CCO)c1
Product: CS(=O)(=O)Nc1cccc(CCOS(C)(=O)=O)c1

Procedure:
The title compound was prepared from 3-aminophenethyl alcohol (U.S. Pat. No. 2,641,602) and methanesulfonyl chloride (2 eq.) according to the procedure contained within description 4. The product was used immediately without further purification or characterisation.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:21])=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>>[ClH:30].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH2:21])=[O:17])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(C(=O)NC(=O)[C@@H](N)Cc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To the compound (I) (2.84 g), 4 N hydrogen chloride/1,4-dioxane solution (35 ml) under room temperature was added and the mixture was stirred at the same temperature for 2 hours. The mixture was concentrated under a reduced pressure, and the residue washed with ethyl ether, followed by filtration to give N-(4-aminomethylbenzoyl)-L-phenylalanine amide hydrochloride (2.32 g) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH-:24]>>[CH3:20][O:21][CH2:22][CH2:23][NH:24][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: COCC[NH-]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCOC)s2)c(C)[nH]c1=O
Yield: 26 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-methoxyethyl)amide as described in Step 5, Example 24 to give the title compound as a solid (26% yield). LC/MS: RT 2.51 min; m/e 357 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 7.97 (1H, t), 7.54 (1H, d), 7.33 (1H, s); 7.16 (1H, d), 3.34 (2H), 3.32 (3H, s), 3.01 (2H), 2.39 (2H, q), 2.31 (3H, s), 1.07 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[Br:15]Br>O>[Br:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Reaction time: 5 h
Yield: 170.7 %

Procedure:
4-Nitrophenol (5 g, 35.9 mmol) was added to acetic acid (20 ml) and to the mixture, there was slowly added a solution of a mixture of bromine (0.93 ml, 18 mmol) and acetic acid (5 ml) at 85° C. The reaction mixture was stirred at the same temperature for 5 h and, thereafter, it was added to water and subjected to extraction with ethyl acetate. The organic extract was concentrated and the residue was subjected to column chromatography using a 7:3:1 solvent system of cyclohexane, ethyl acetate and methanol as an eluent to yield the end compound 2-bromo-4-nitrophenol (6.7 g).