Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:26])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(Cl)Cl>[C:3]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:26])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(CN1CCC(N)CC1)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CN1CCC(NC(=O)C2CC2)CC1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
A stirred solution of 1-[2-(4-benzoylphenyl)propyl]-4-aminopiperidine dihydrochloride, 150 ml. of methylene dichloride and 10.5 g. (0.105 mole) of triethylamine was treated in portions with a solution of 3.9 g. (0.039 mole) of cyclopropanecarbonyl chloride in methylene dichloride. When addition was complete the mixture was allowed to stand at ambient temperature for twenty-four hours and then washed two times with water, once with aqueous potassium carbonate and once with brine and then dried and taken to dryness in vacuo. Recrystallization of the residue from diethyl ether gave 1-[2-(4-benzoylphenyl)propyl]-4-cyclopropanecarbonylaminopiperidine, m.p. 159°-160° C.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:29]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2([CH2:1][CH2:2][OH:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:20][CH:21]=1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccccc2)C(=O)O1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](c1ccccc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one (0.1016 g, 0.30 mmol, 1.0 equiv) in THF-H2O (1:1, 6 mL) were added NaIO4 (0.3240 g, 1.5 mmol, 5 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.0507 g, 0.0049 mmol, 0.016 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g) was added. After the mixture was stirred for 1.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([OH:21])[C:18]=1[CH2:19][OH:20].[CH2:23](I)[CH3:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([O:21][CH2:23][CH3:24])[C:18]=1[CH2:19][OH:20]
Reactant: Cc1ncc(Cn2cnc3c(Cl)nc(N)nc32)c(CO)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C)ncc(Cn2cnc3c(Cl)nc(N)nc32)c1CO
Temperature: 50 °C

Procedure:
A mixture of 6-chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine (see previous example), EtI (excess), K2CO3 (excess) and DMF was heated to 50° C. for 15 min. Work-up (EtOAc), drying (MgSO4), evaporation, and purification by preparative TLC gave the title compound. HPLC Rt: 3.720 min. 1H-NMR (CDCl3) δ 8.27 (s, 1H), 7.90 (s, 1H), 5.40 (s, 2H), 5.11 (s, 2H), 4.85 (d, 2H), 4.50 (t, 1H), 3.95 (q, 2H), 2.51 (s, 3H), 1.45 (t, 3H).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O-]CC.[Na+].[Na].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C(O)C.C(Cl)(Cl)Cl>[O:17]=[C:16]([CH3:18])[CH2:14][CH2:15][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: C=CC(C)=O
Reactant: CCOP([O-])OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOP(=O)(CCC(C)=O)OCC
Temperature: 15 °C

Procedure:
To 243 grams (1.76 moles) of diethyl phosphite stirred under nitrogen and protected by a drying tube was added a solution of sodium ethoxide prepared from 5.07 grams (0.22 mole) of sodium in 100 ml of anhydrous ethanol. Methyl vinyl ketone, 112 grams (1.60 moles), was then added at such a rate as to keep the temperature at 35°-40° C. The addition required about one hour. The reaction mixture was stirred for one-half hour after the addition was completed and was stripped to dryness in vacuo at 60° C./16 mm. The residue was taken up in 600 ml of chloroform, and the solution cooled to 15° C. and washed successively with dilute acid, water and saturated sodium chloride solution. After drying, the chloroform solution was distilled to yield 112 grams of diethyl 3-oxobutylphosphonate as a colorless liquid, B.P. 106° C./0.05 mm, nD 25 1.4340. VPC indicated that the product was 90% pure.
Reaction SMILES: [Br-:1].Cl[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6].[CH:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:38][CH:39]=1>C(#N)C>[Br-:1].[C:37]1([N:40]2[CH2:45][CH2:44][N:43]([CH2:3][CH2:4][C:5]([NH:7][C:8]3[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=3[CH2:10][P+:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:6])[CH2:42][CH2:41]2)[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCl)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: O=C(CCN1CCN(c2ccccc2)CC1)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 2-(3-chloropropionylamino)benzyltriphenylphosphonium bromide (2.70 g, 5 mmol) and phenylpiperazine (1.70 g, 10 mmol) in acetonitrile (85 ml) was heated at reflux for 2.5 h. The mixture was cooled to room temperature and filtered and the filtrate evaporated in vacuo to give 2-(3-[4-phenylpiperazin-1-yl]propionylamino) benzyltriphenylphosphonium bromide as a white solid (3.1 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Cl)=[C:8]([CH2:10]Cl)[CH:9]=1)=[O:4].[S-2:14].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:12][S:14][CH2:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: [S-2]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(s1)CSC2
Yield: 49.9 %

Procedure:
A solution of 4.8 g (20 mmol) (2) in 240 mL methanol was heated up and kept mild boiling. Sodium sulfide solution (1.7 g, 22 mmol) in 160 mL methanol was added dropwise in 2 h. After cooling of the reaction mixture, the precipitate was filtered off. The solvent was removed by evaporation and the residue was washed by water. Column chromatography on silica gel using dichloromethane yielded the pure title compound as a white solid 2.0 g (50%). 1HNMR (CDCl3): δ 3.87 (3H, s), 4.05-4.06 (2H, t, J=3 Hz), 4.19-4.20 (2H, t, J=3 Hz), 7.48 (1H, s). 13CNMR (CDCl3): 633.12, 33.47, 52.19, 127.90, 137.30, 143.90, 146.64, 162.51.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:26]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:8]2[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6](=[O:25])(=[O:24])[C:7]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.4 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.150 mg, 0.413 mmol), benzoic acid (0.055 g, 0.454 mmol), EDC (0.087 g, 0.454 mmol), HOBt (0.061 g, 0.454 mmol) and TEA (0.120 ml, 0.825 mmol) in THF (3 ml) was stirred at rt for 3.5 h. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.136 g, 71%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.42 (m, 5H), 7.42-7.35 (m, 2H), 7.32-7.29 (m, 1H), 5.21 (d, 1H), 4.48 (bs, 1H), 3.56 (bs, 1H), 3.24-3.12 (m, 1H), 2.58-2.44 (m, 2H), 1.90-1.64 (bs, 2H), 1.74 (s, 9H), 1.48-1.16 (bs, 2H); 13C NMR (125 MHz CDCl3): δ 170.6, 159.7, 135.7, 133.9, 131.8, 130.2, 130.0, 128.9, 128.7, 126.9, 125.2, 107.7, 61.9, 50.4, 27.8; Mass Spectrum: M+H+ 468.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([CH3:24])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: C(OC[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)C=C.ClC1C=CC(CN2C3C(=[C:33]([CH2:38][OH:39])C=CC=3)C=C2)=CC=1.C(Br)C=C.[H-].[Na+]>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:10]2[C:11]3[C:7](=[C:6]([CH:38]([OH:39])[CH3:33])[CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)=[CH:21][CH:20]=1
Reactant: C=CCOCc1cccc2c1ccn2Cc1ccc(Cl)cc1
Reactant: OCc1cccc2c1ccn2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: CC(O)c1cccc2c1ccn2Cc1ccc(Cl)cc1

Procedure:
2-[4-[(allyloxy)methyl]-1-(4-chlorobenzyl)-1H-indole, oil (prepared by alkylation of [1-(4-chlorobenzyl)-1H-indol-4-yl]methanol with allyl bromide in DMF in the presence of NaH, at room temperature for 3 h).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:21]=[CH2:22])=[N:10]2)[CH:5]=[CH:4][CH:3]=1>CCO.C(Cl)Cl.[OH-].[Pd+2].[OH-]>[CH2:21]([C:11]1[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][C:17]=2[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[N:10]=1)[CH3:22]
Reactant: C=Cc1nn(Cc2cccc(C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To 1-((6-methylpyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole (28.2 g, 95.8 mmol, Example 5, step C) in EtOH/DCM (300 mL/10 mL) was added palladium hydroxide (15 g, 20% wt). The reaction was purged with N2 and charged with hydrogen to 45 psi. The reaction was recharged during the reaction to 45 psi 4-5 times for the first 30 minutes. After 2 hours, the reaction was stopped, filtered through Celite, and the filter pad was washed with MeOH/DCM/Et3N (1 L, 10:1:1). The filtrate was concentrated and silica gel chromatography (EtOAc/hexanes 1:3) to provide the desired product (22.4 g).
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=2)=[CH:6][N:5]=1.O.[OH:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23]>>[C:10]([C:9]1[C:4]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][OH:25])=[N:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=2)[CH:8]=1)#[N:11]
Reactant: OCC(O)CO
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1OCC(O)CO

Procedure:
300 mg Potassium hydroxide is dissolved in 15 ml glycerin with heating and 1 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide is subsequently added. The reaction mixture is heated for 3 hours at 80° C.-90° C. with stirring, allowed to cool and treated with water. The precipitate obtained is filtered off with suction. Yield: 2 g (89.5% of the theoretical yield), having a melting point of 194° C.-196° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzoic acid (4.9 g, 35.3 mmol), benzyl bromide (3.8 mL, 31.7 mmol), and cesium carbonate (17.2 g, 53 mmol) in DMF (50 mL,) at room temperature was stirred for 24 hours, diluted with water, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1C(O)=O.OCCS(C1C=CC(OC2C=CC(S)=CC=2)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>C1C=C(Cl)C(Cl)=CC=1>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(CCO)c1ccc(Oc2ccc(S)cc2)cc1
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-carboxy-4-bromoanthraquinone (6.9 parts) and 4-(4'-β-hydroxyethylsulfonylphenoxy)thiophenol (6.5 parts) were allowed to react with each other at 100° to 120° C. in O-dichlorobenzene in the presence of cuprous chloride and potassium carbonate. Thereafter, methanol was added to the reaction mixture to deposit solids, which were collected on a filter, washed throughly with methanol and water and then dried at 80° C. The resulting product was subjected to sulfonation and esterification simultaneously at 20° to 40° C. in 14% oleum. Thereafter, ice was added thereto, and the solids deposited were collected on a filter, thereby obtaining an anthraquinone compound of the following formula (free acid form). ##STR383##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1C=O)[CH3:2].[O-][CH2:28]C.[Na+].Cl>C(=O)(OCC)OCC.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:28]=1)=[O:26])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(OCC)cc2)cc1C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C1=Cc2cc(-c3ccc(OCC)cc3)ccc2OCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 4-[(4′-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxy]butyric acid ethylester (0.50 g) in diethyl carbonate (5 ml) was added a solution of 20% sodium ethoxide in ethanol (0.57 g) at room temperature, and the mixture was then heated to 50° C. and stirred for 1 hour. The solution was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed, and concentrated. The concentrate was purified by silica gel chromatography (n-hexane/ethyl acetate=10/1) and subsequent concentration of the appropriate eluate gave white crystal of the title compound (0.39 g, yield 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:22][C:23]([N:25]1[CH2:34][CH2:33][C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[CH2:29]1[C:28]2([CH2:33][CH2:34][N:25]([C:23](=[O:24])[CH2:22][N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[O:10])[CH2:26][CH2:27]2)[CH2:32][CH2:31][CH2:30]1
Reactant: NCC(=O)N(CC(=O)N1CCC2(CCCC2)CC1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCC3(CCCC3)CC2)c2ccccc2)c1
Reaction time: 12 h
Yield: 41.5 %

Procedure:
0.49 g of 3-methylphenyl isocyanate is added at a temperature close to 25° C to a solution of 1.2 g of 2-amino-N-[2-(8-azaspiro[4,5]decan-8-yl)-2-oxoethyl]-N-phenylacetamide in 50 cm3 of anhydrous tetrahydrofuran. The mixture is stirred for 12 hours at a temperature close to 25° C and the insoluble product is separated off by filtration. After recrystallization from ethyl acetate, 0.7 g of N-[2-(8azaspiro[4,5]decan-8-yl)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 183° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[C:45]([N:42]1[CH2:41][CH2:40][N:39]([C:36]2[CH:37]=[CH:38][C:33]([NH:32][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([S:28]([NH2:31])(=[O:29])=[O:30])[CH:25]=[CH:26][CH:27]=4)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)=[CH:34][CH:35]=2)[CH2:44][CH2:43]1)(=[O:47])[CH3:46]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(S(N)(=O)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.210 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 72 h. More 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide (40 mg)
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Br:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Br
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Br)C(F)(F)F
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.75 g) in N,N-dimethylacetamide (10 mL) was rapidly added thionyl chloride (0.56 g) and the mixture stirred at -15 to -20° C. for 1 hour. 3-Bromo-4-aminobenzophenone (0.75 g) was then added in one portion and the mixture was allowed to stir at room temperature overnight. The solution was poured into ice water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent methylene chloride) gave the title compound (0.43 g) as a white solid; mp 138-40° C. Analysis for C17H13BrF3NO3 : Calculated: C, 49.06; H, 3.15; N, 3.37; Found: C, 49.06; H, 3.10; N, 3.35.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:17]1([NH:20][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (670 mg, 2.92 mmol) and cyclopropylamine (167 mg, 2.92 mmol) in 15 mL anhydrous DMF was added HATU (1.11 g, 2.92 mmol) and the resulting mixture stirred at RT under nitrogen atmosphere for 3 h. The mixture was washed with water and extracted with ethyl acetate (2×50 mL). The organics were washed with brine, separated, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by Biotage MPLC (silica gel 40+ column) eluting with 50% ethyl acetate in hexane to afford the product (704 mg, 89%). ESI-MS calculated for C14H24N2O3: Exact Mass: 268.18. Found 169.17 (M-Boc)+ and 291.15 (MNa)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]([OH:24])([CH3:23])[CH:7]=[CH:8][CH:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:25]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:10]1[CH:9]([CH:8]=[CH:7][C:6]([OH:24])([CH3:23])[CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:13][CH2:12][C:11]1=[O:14])(=[O:27])[CH3:26]
Reactant: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCOC(C)=O
Reaction time: 72 h

Procedure:
A solution of 7-[2-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol [0.4 g; prepared as hereinbefore described in Example 7(iv)] in dry pyridine (4 ml.) was treated with acetic anhydride (4 ml.) and the resulting solution was allowed to stand at ambient temperature for 3 days and then diluted with water (100 ml.) with external cooling by means of an ice-bath. The resulting aqueous solution was extracted three times with chloroform, and the combined extracts were dried over sodium sulphate. Evaporation in vacuo gave a crude product which was purified by preparative thin layer chromatography on silica gel using a mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, to give 2-(7-acetoxyheptyl)-3-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)cyclopentanone (0.17 g.).