Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+:2].[C:3]([O:15]C)(=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C1C=CC=CC=1>CO>[C:8]([O:10][CH3:11])(=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:3]([O-:15])=[O:14])=[CH:5][CH:6]=1.[K+:2]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(=O)[O-])cc1

Procedure:
Potassium monomethyl terephthalate was prepared by adding dropwise a solution of 85.5 grams (1.286 mole) potassium hydroxide (85% pellets) in 675 ml methanol to a stirred solution of 250 grams (1.286 mole) of dimethyl terephthalate in 1600 ml. of benzene at 60° C. over 1 hour. The mixture was refluxed for 15 minutes, cooled, and filtered. The white solid on the filter was washed with acetone and sucked dry. It weighed 263 grams (93 mole % yield). It did not melt below 400° C.
Reaction SMILES: C[O:2][C:3]1[C:13]2[C:14]3[C:6]([CH2:7][CH:8]([N:15]4[CH2:20][CH2:19][CH:18]([N:21]5[C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=6[N:23]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[C:22]5=[O:35])[CH2:17][CH2:16]4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC(C)=O>[OH:2][C:3]1[C:13]2[C:14]3[C:6]([CH2:7][CH:8]([N:15]4[CH2:16][CH2:17][CH:18]([N:21]5[C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=6[N:23]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[C:22]5=[O:35])[CH2:19][CH2:20]4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)Cn1c(=O)n(C2CCN(C3Cc4ccc(OC)c5cccc3c45)CC2)c2ccccc21
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CNC(=O)Cn1c(=O)n(C2CCN(C3Cc4ccc(O)c5cccc3c45)CC2)c2ccccc21
Temperature: -50 °C

Procedure:
2-{3-[1-(5-Methoxyacenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide (780 mg) was dissolved in dichloromethane (50 ml), a solution (8.0 ml) of boron tribromide (1.0 mol) in dichloromethane was added dropwise under a nitrogen stream while cooling to −50° C., and the mixture was gradually warmed over 1 hr. After completion of the reaction, the reaction mixture was poured into an aqueous potassium carbonate solution by small portions, during which unnecessary substances were dissolved in acetone), the mixture was extracted with chloroform, and the extract was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH-coating silica gel column chromatography to give a crude product of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[C:13]1([CH2:19][SH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH2:19]([S:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]nc(SCc2ccccc2)c2ccccc12
Reaction time: 2 h
Yield: 61.3 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (500 mg, 2.77 mmol), phenylmethanethiol (412 mg, 3.32 mmol) and sodium hydride (144 mg, 3.6 mmol) in DMF (30 mL) was stirred at 125 C for 2 hours. The reaction mixture was quenched with water, and extracted with EtOAc (2×). The combined organic layer was washed with water, and concentrated to give 456 mg (61%) of title compound. MS (APCI+) M/Z 269 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O>N1C=CC=CC=1>[C:1]1([O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccccc1O
Solvent: c1ccncc1
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
A toluene para-sulfonyl derivative of compound 14 was transformed with methoxyphenol in pyridine to give the diphenylether (compound 15) at 75% yield. Catalytic reduction of the nitro groups was carried out quantitatively in ethanol in order to allow the diamino derivative (compound 16) to be tetrazotized at 0° C. The resulting tetrazolium salt was reacted with sodium iodide to give the 3,5-diiodo compound in good yield (compound 17). Due to difficulties with hydrolysis, complete acidolysis of the ester was done under reflux using hydriodic acid (HI) as a strong cleaving agent, which removed both the ester and the O-methyl groups. Acetic acid was added to this reaction instead of H2SO4 to avoid decomposition of HI into I2. Tetrac (compound 8) was then obtained by two displacements of a proton from the aromatic nucleus of the di-iodoacid (compound 18) by an iodide. In that reaction, the iodo-deprotonation was carried out using I2 in methanolic NH3 in 91% yield. Of note, complete acidolysis of compound 17 revealed some advantage; thereafter aminolysis of the ethyl ester and formation of an amide during the iodination reaction was avoided. Also, selective iodination on the outer ring benefited from the transformation of the methyl ether group into an alcohol. This was done to allow activation of the ortho position by oxygen through inductive and resonance effects.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[CH:26][C:27]=1[CH2:28]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:27]5[CH:26]=[C:25]([Cl:30])[S:24][C:23]=5[Cl:22])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1cc(Cl)sc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)sc4Cl)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2,5-dichloro-3-thienyl)methanol (130 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (39.9 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:23][CH3:24])[C@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]4.C(=O)([O-])[O-].[K+].[K+].[N:31]#CBr>C(Cl)Cl>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([O:23][CH3:24])[C@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]3)#[N:31]
Reactant: N#CBr
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Yield: 99.9 %

Procedure:
To a solution of 3,14-dimethoxy-8α,17-dimethylmorphinan-6-one (24) (0.1 g, 0.303 mmol) in methylene chloride (3 ml) was added anhydrous potassium carbonate (0.23 g) followed by cyanogen bromide (0.2 g). The mixture was refluxed overnight under a nitrogen atmosphere with stirring. After cooling, the solution was filtered and the residue washed with excess methylene chloride. The filtrate was concentrated under reduced pressure to give 0.103 g (99% theory) of 17-cyano-3,14-dimethoxy-8α-methylmorphinan-6-one (25) as a foamy solid. Examination by thin layer chromatography showed a single spot (silica gel plates; solvent system CHCl3 :MeOH, 90:10). The product was used in the next reaction without purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@@H:35]([C:37](O)=[O:38])[CH3:36])(OCC1C=CC=CC=1)=O>>[NH2:34][C@H:35]([CH3:36])[C:37]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:38]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: C[C@@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method B and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-D-alanine as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.04 (m, 1H), 3.89 (q, J=6.9 Hz, 1H,), 3.39 (dd, J=5.7, 13.5, 1H), 3.23 (dd, J=5.4, 13.5 Hz, 1H,), 1.85 (m, 2H), 1.77-1.62 (m, 6H), 1.57-1.53 (m, 2H), 1.48 (d, J=6.9 Hz, 3H), 1.37-1.15 (m, 3H), 1.08-0.97 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 43.74. LCMS m/z: [M+H]+=307.2.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:16]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[NH2:28])=[CH:21][CH:20]=1)[CH3:18])([O:14][CH3:15])=[O:13]>>[C:12]([CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([NH:28][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:30])[CH3:29])=[CH:23][CH:24]=1)[CH3:18])([O:14][CH3:15])=[O:13]
Reactant: O=CC(=O)c1ccccc1
Reactant: COC(=O)C=C(C)c1ccc(CCC(C)(C)N)cc1
Solvent: O
Product: COC(=O)C=C(C)c1ccc(CCC(C)(C)NCC(O)c2ccccc2)cc1
Yield: 64.6 %

Procedure:
This was prepared in an identical manner to the compound described in Example 13 using phenylglyoxal monohydrate (1.34 g) and 3-{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1, 1-dimethylpropanamine (2.61 g). The title compound (2.17 g) m.p. 98°-102° C. (benzene-hexane) was obtained after chromatography on Kieselgel 60 eluting with 1% methanolchloroform. τ(CDCl3) 8.85 (6H, s), 8.1-8.7 (2H, m), 6.8-7.8 (9H, m), 6.2 (3H, s), 5.3 (1H, dd), 3.82 (1H broad), 2.65 (9H, m).
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH2:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:34]([OH:36])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:37][N:38]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>O.CN(C)C=O>[OH:37][NH:38][C:34]([CH:11]1[CH2:10][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH2:33])=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:36]
Reactant: C=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: C=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)NO)cc1
Yield: 40.1 %

Procedure:
The procedure of Example 45 was followed using the product from Example 43 (230 mg, 0.456 mmol), 1-hydroxybenzotriazol (111 mg, 0.821 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (157 mg, 0.821 mmol), hydroxylamine in water 50% solution (0.251 ml, 4.1 mmol) in dimethylformamide (3 ml) to give 95 mg (40%) of the product.
Reaction SMILES: C(O[K])(C)(C)C.[Br:7][C:8]([F:15])([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>CCCCCC>[Br:7][C:8]([F:15])([F:14])[C:9]([O:11][CH2:12][C:13]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: OCc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)C(F)(F)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
1.60 g (14 mmol) of t-butoxypotassium was added to a solution prepared by dissolving 20.30 g (0.1 mol) of ethyl 2-bromo-2,2-difluoroacetate in 140 ml of benzyl alcohol and 1200 ml of hexane at 0° C. in a nitrogen atmosphere. The mixture was stirred at 0° C. for 1 hour. After confirming disappearance of the raw materials by thin-layer chromatography (TLC), the reaction was terminated by adding 120 ml of concentrated hydrochloric acid. The mixture was washed twice with water, washed twice with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the product was purified by column chromatography to obtain 15.37 g of benzyl 2-bromo-2,2-difluoroacetate shown by the following formula (yield: 58%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CS(C)=O>[C:12]1([NH:11][C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[NH:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N=C(Nc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% in mineral oil, 11.52 g, 288 mmol) was added portion-wise over 30 min to a stirred solution of 3-pyridinecarbonitrile (30 g, 288 mmol) and aniline (26 g, 290 mmol) in dimethylsulfoxide (150 mL) at 10° C. The reaction mixture was allowed to warm to ambient temperature with stirring for 18 h. The reaction mixture was slowly and cautiously poured into water containing crushed ice. The solid that precipitated was filtered, washed with petroleum ether, dissolved in dichloromethane and dried over anhydrous Na2SO4. The volatiles were removed under reduced pressure (high vacuum) and the residue was dried to afford 36.5 g of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:4]=2[O:3]1.[Br:15][CH2:16][CH2:17]Br>C(O)(C)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:13][CH2:17][CH2:16][Br:15])=[CH:12][C:4]=2[O:3]1
Reactant: BrCCBr
Reactant: CC1(C)NC(=O)c2ccc(O)cc2O1
Solvent: CC(C)O
Product: CC1(C)NC(=O)c2ccc(OCCBr)cc2O1

Procedure:
16.2 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one are reacted analogously to Example (3a) with 84 ml of 1,2-dibromoethane and yield 2,3-dihydro-2,2-dimethyl-7-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one having a melting point of 156°-158° (from isopropanol).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[C:10](O)[CH:11]=[CH:12][C:13]=3O)[C:7](=[O:8])[C:5]=2[CH:6]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:10]2[C:9]3[C:7](=[O:8])[C:5]4[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=4)[C:15](=[O:16])[C:14]=3[C:13]([NH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)[CH2:23][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: NCCN1CCOCC1
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCOCC3)ccc(NCCN3CCOCC3)c21

Procedure:
A 9.60 g. portion of quinizarin, 46.90 g. of N-(2-aminoethyl)morpholine and 56 ml. of water are reacted as described in Example 1 giving 9.92 g. of the desired product as a blue-black solid, mp. 158°-159° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:25])[N:15]=[C:14]2[S:26][C:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:13]=12)[CH:2]=[CH2:3].C(O[C:37]([CH3:40])([CH3:39])[CH3:38])(=O)C.S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([O:24][C:37]([CH3:40])([CH3:39])[CH3:38])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:25])[N:15]=[C:14]2[S:26][C:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:13]=12)[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: C=CCOc1cc(C)ccc1-c1c(C(O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C=CCOc1cc(C)ccc1-c1c(C(OC(C)(C)C)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a stirred solution of ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(hydroxy)acetate (Step 7, 720 mg, 1.59 mmol) in dichloromethane (2.5 mL) was added tert-butyl acetate (2.5 mL) followed by concentrated sulphuric acid (244 μL, 4.78 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition of a 1 M aqueous sodium hydroxide solution until the solution was at pH 5. The volatile solvents were removed in vacuo, and the remaining aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 40%). Product containing fractions were concentrated in vacuo to give a mixture of diastereoisomers of the title compound as a colourless oil, 370 mg, in a 45% yield. Material is shown to be a mixture of diastereomers, in an approximately 80:20 ratio.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: O=C1CCCCC1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1=CCCCC1
Temperature: 120 °C

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole (1 g, the compound of Reference Example 1 from EP 295,117) and cyclohexanone (1.6 ml) in acetic acid (5 ml) was stirred and heated at 120° C. overnight under an atmosphere of nitrogen. The cooled reaction mixture was diluted with water and extracted with ethyl acetate and then ether. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then water. After drying (MgSO4), evaporation gave the crude product which was purified by column chromatography on silica gel (50 g) eluted with dichloromethane:hexane (1:2), then dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions provided the title compound as a white solid m.p. 175-7° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C1COCC1>[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][N:26]([C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:25]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrobenzoyl chloride (1.8 g, 10 mmol) and diisopropylethylamine (2.8 mL, 20 mmol) in THF at room temperature is added 3-(dimethylamino)pyrrolidine (1.4 mL, 11 mmol). The reaction is stirred for 2 hours at room temperature and concentrated in vacuo to give 3-dimethylamino-1-(4-nitrobenzoyl)pyrrolidine, identified by HPLC and MS [264.3 m/e (M+H)] analyses.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([CH2:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1.N1C=CC=CC=1>O>[CH:5]1([CH2:13][Br:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: OCC1C=CCCCCC1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: O
Product: BrCC1C=CCCCCC1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
A solution of phosphorus tribromide (1.02 cm3 ; 0.0105 m) in 40 to 60 petroleum ether (5 cm3) was added dropwise to a solution of 2-cyclooctenylcarbinol (2.8 g; 0.02 m) (fraction 9 above) and AR. Pyridine (0.104 g; 0.0013 m) in petroleum ether (15 cm3) stirred and cooled to -10° C. After addition the mixture was allowed to warm to room temperature and stood for 2 days. The reaction mixture was treated with water (50 cm3) and the organic layer separated. The aqueous layer was extracted with 40 to 60 petroleum ether (3×25 cm3) and the combined organic layer and petrol extracts washed with 2 N-NaOH (25 cm3) and water (25 cm3). The petrol extracts were combined and dried over anhydrous MgSO4 and the solvent removed under vacuum to leave a crude product 2.3 g. The crude product was distilled to give 0.7 g of pure product b.p. 48°-50°/0.25 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:28](=[O:30])[NH2:29].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:28](=[O:30])[NH2:29]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A solution of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (47.9 mg, 0.118 mM) and 0.28 mL (0.28 mM) of 1 N NaOH in 10 mL of methanol was sonicated for 6 hours at 50-60° C., then stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to afford 42.8 mg (92%) of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.5-7.25 (m, 6H), 7.15 (d, 1H, J=8 Hz), 7.05 (dt, 1H, J=1 and 8 Hz), 6.75 (dt, 1H, J=1 and 8 Hz), 6.65 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3428, 3400, 1737, 1635, 1617, 1583, 1572, 1500, 1491, 1453, 1434, 1330, 1248, 1158, 1098, 760, and 714. MS (FD) m/e 392.