Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)[CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:29]1[N:30]=[C:26]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[S:27][CH:28]=1)=[O:32]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1csc(-c2cccnc2)n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-3-yl-thiazole-4-carboxylic acid. MS: 448.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1cncc(C2CCCN2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccnc2)cc1

Procedure:
The title compound, white solid, m.p. 112° C., and MS: m/e=302 (M+) was prepared in accordance with the general method of example 1e from 3-(pyrolidin-2-yl)-pyridine and toluene-4-sulfonyl chloride.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[C@H:15]1[C:36]([OH:38])=[O:37])([OH:3])=[O:2].[OH-].[Na+:40]>C(O)C.O>[Na+:40].[Na+:40].[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[C@H:15]1[C:36]([O-:38])=[O:37])([OH:3])=[O:2].[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[C@H:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[C@H:15]1[C:36]([O-:38])=[O:37])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)[O-])[C@H]2c1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
A solution of (+) (1S, 2R, 3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid in absolute ethanol/water (12 to 1) was titrated to pH=11-12 with 1.25 N sodium hydroxide solution then after stirring for 15 minutes, concentrated to an oil. Absolute ethanol was added and the solution reconcentrated to a solid which was triturated with hexane, and filtered. The solid was dried to constant weight to afford (+) (1S, 2R, 3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([Br:19])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: CN1CCC(O)CC1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(Br)cc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL), at 65° C., was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 1 h, a solution of 1,3-dibromo-5-fluorobenzene (1.26 mL, 10.0 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 3 days. The mixture was allowed to cool to ambient temperature then poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL) and loaded onto an SCX-2 cartridge, which was then washed with acetonitrile and eluted with 2N ammonia in methanol. Concentration of the basic methanolic fraction in vacuo gave the title compound (1.88 g, 54%). 1H NMR (CDCl3, 400 MHz): 7.22 (t, J=1.6 Hz, 1H), 6.98 (d, J=1.7 Hz, 2H), 4.31-4.23 (m, 1H), 2.69-2.59 (m, 2H), 2.37-2.18 (m, 5H), 2.01-1.92 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.3 min, M+H+=350.
Reaction SMILES: [C:1]([N+:4]1([O-:26])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:28]1[CH:29]=CC2C(=C3CCN(C(=O)C)CC3)C3NC(=O)C=CC=3CC[C:32]=2[CH:52]=1>>[C:1]([N+:4]1([O-:26])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]4[C:24](=[CH:25][C:11]2=3)[CH:32]=[CH:52][CH:28]=[CH:29]4)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc(=O)[nH]c32)CC1
Reactant: CC(=O)[N+]1([O-])CCC(=C2c3ccccc3CCc3cc(Cl)cnc32)CC1
Product: CC(=O)[N+]1([O-])CCC(=C2c3cc4ccccc4cc3CCc3cccnc32)CC1

Procedure:
1-acetyl-4-(3-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine N-oxide, i.e., ##STR9## 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-2(1 H)-one;
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])(O)(O)=O.[K+].S([O-])([O-])(=O)=O.[Mg+2].[O:25]=[C:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:27][C:28]([O-:30])=[O:29].[K+].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[OH:25][C@H:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCC(=O)CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: O
Product: CCCCCCC[C@@H](O)CC(=O)O
Temperature: 25 °C

Procedure:
Baker's yeast (Saccharomyces cerevisiae, Malteserkors®, De danske Spritfabrikker, 640 g), D-glucose (720 g), potassium dihydrogenphosphate (1.6 g) and magnesium sulfate (0.8 g) in water (2 l) were stirred at room temperature for 30 minutes. A solution of the above potassium 3-oxodecanoate in water (1.5 l) was added. The mixture was stirred at ambient temperature and pH was kept between 6.0 and 6.5 by automatic titration with 1M potassium hydroxide or 1M citric acid. After 48 hours Celite® was added, and after stirring for 30 minutes more the mixture was filtered. The filtrate was acidified to pH 2.5 with concentrated hydrochloric acid, extracted with methylene chloride (2×2 l), dried and evaporated in vacuo to give crude 3(R)-hydroxydecanoic acid.
Reaction SMILES: C([O:4][C:5](=[O:49])[CH:6]([NH:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]([N:29]2[C:35]3[CH:36]=[C:37]([O:42][CH3:43])[C:38]([O:40][CH3:41])=[CH:39][C:34]=3[C:33](=[O:44])[N:32]3[CH2:45][CH2:46][CH2:47][C@H:31]3[C@@H:30]2[OH:48])=[O:28])=[CH:21][CH:20]=1)=[O:17])[CH2:7][CH2:8][C:9]([O:11]CC=C)=[O:10])C=C.N1CCCC1>C(Cl)Cl.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>[CH3:41][O:40][C:38]1[C:37]([O:42][CH3:43])=[CH:36][C:35]2[N:29]([C:27]([O:26][CH2:25][C:22]3[CH:21]=[CH:20][C:19]([O:18][C:16]([NH:15][CH:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5]([OH:49])=[O:4])=[O:17])=[CH:24][CH:23]=3)=[O:28])[C@@H:30]([OH:48])[C@@H:31]3[CH2:47][CH2:46][CH2:45][N:32]3[C:33](=[O:44])[C:34]=2[CH:39]=1
Reactant: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)N2c3cc(OC)c(OC)cc3C(=O)N3CCC[C@H]3[C@@H]2O)cc1)C(=O)OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccc(OC(=O)NC(CCC(=O)O)C(=O)O)cc1)[C@@H](O)[C@@H]1CCCN1C2=O
Yield: 80.5 %

Procedure:
A solution of the diallyl ester 45 (0.596 g, 0.95 mmol, 1 eq), Pd(PPh3)4 (0.055 g, 0.047 mmol, 0.05 eq) and pyrrolidine (0.34 g, 0.39 mL, 4.7 mmol, 5 eq) in anhydrous CH2Cl2 (18 mL) was stirred at room temperature for 1 h and the solvent removed in vacuo. The residue was washed with EtOAc (3×15 mL), dissolved in MeOH (15 mL) and passed down an IRC 50, weakly acidic, ion exchange column, eluting with MeOH (80 mL). The solvent was removed in vacuo to give the product as a white foam (0.46 g, 88%). 1H NMR (d6 DMSO) δ 7.95 (d, J=6.25 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.10 (m, 3H) 6.73 (s, 1H), 5. 49 (d, J=9.2 Hz, 1H), 5.2 (d, J=12.5 Hz, 1H), 4.89 (d, J=12.75 Hz, 1H), 4.00 (m, 1H), 3.80 (m, 7H), 3.45 (m, 4H) 2.30 (t, J=7.5 Hz, 2H), 1.95 (m, 5H). MS (ES+) 602.2.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[H-].[Na+].[OH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.Cl>C1COCC1>[CH2:1]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[O:19])=[CH:20][CH:21]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(OCCOCCO)cc1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
All three compounds were prepared by the etherification of the corresponding alcohols with allyl bromide. An example is presented below. Sodium hydride (3.06 g, 0.128 mol) was suspended in dried THF (150 mL). The solution was bubbled with nitrogen and cooled to 0° C. 4-[2-(2-Hydroxyethoxy)ethoxy]benzaldehyde (26.8 g, 0.128 mol) was added dropwise to the solution. After the addition was completed, the resulting solution was stirred for 0.5 hr. Allyl bromide (23.2 g, 0.191 mol) was added. The reaction mixture was stirred at room temperature for 3 hr, acidified with 5% HCl aqueous solution (100 ml) and extracted with ethyl acetate. The collected organic phase was washed with 2% sodium bicarbonate aqueous solution, water, saturated sodium chloride solution, and dried over anhydrous MgSO4. The solvent was evaporated in a rotavapor and the residual oil was vacuum distilled at 136° C./7 mmHg to yield 20 g (63%) of a colorless oily product 6. 1 H-NMR (CDCl3, TMS, δ in ppm): 3.56-4.27 (m, 10H, --CH2 --(O--CH2 --CH2)--2), 5.23 and 5.78 (m, 3H, CH2 =CH--), 7.05 and 7.77 (2d, 4 aromatic protons), 9.86 (s, 1H, --CHO).
Reaction SMILES: [CH3:1][CH:2]([S-:4])[CH3:3].[Na+].Cl[C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH3:21])[CH:8]=1>CO>[CH3:21][C:9]1[CH:8]=[C:7]([S:4][CH:2]([CH3:3])[CH3:1])[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=1
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SC(C)C)c2ccc3cccnc3c2n1
Yield: 80 %

Procedure:
Solid sodium 2-propanethiolate (2.35 g, 24.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, MeOH/DCM, 1:80) to afford the pure product as a yellow oil (1.03 g, 80%).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:18]2=[N:19][NH:20][C:21](=[O:26])[C:22]3[CH:23]=[CH:24][CH:25]=[C:16]([C:17]=32)[NH:15][CH:14]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH:10]1[CH:11]=[CH:12][N:8]=[C:9]1[CH:13]1[C:18]2=[N:19][NH:20][C:21](=[O:26])[C:22]3[CH:23]=[CH:24][CH:25]=[C:16]([C:17]=32)[NH:15][CH:14]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1nccn1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ncc[nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (200 mg, 0.48 mmol), 20% Pd(OH)2/C catalyst (100 mg) in methanol (15 mL) was purged with 1 atm hydrogen and stirred at 40° C. over overnight. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was washed with methanol to obtain 9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a light yellow solid (114 mg, yield 72%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:30]=[N:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=3)=[CH:19][CH:18]=2)[CH:6]=[C:5]([CH3:53])[N:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:19][CH:18]=2)[CH:6]=[C:5]([CH3:53])[N:4]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(-c2ccncc2)c(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(-c2ccncc2)c(C)n1
Reaction time: 3 h

Procedure:
6M Hydrochloric acid (1 ml) was added to a solution of 2,6-dimethyl-3-(4-pyridyl)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (A) (800 mg) in dioxan (20 ml) and the mixture was stirred for 3 hours. Volatile material was removed by evaporation and the residue triturated with ether. The ether was separated and the residue was dissolved in methanol. Ether was added to precipitate the product and the solvent was again separated. The residue was then triturated with ether to give 2,6-dimethyl-3-(4-pyridyl)-4-[(2'(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine dihydochloride (0.51 g), as a solid, m.p. 180° C. (decomposition); NMR (d6 -DMSO, d4 -acetic acid): 2.4(s,3H), 2.75(s,3H), 5.45(s,2H), 7.1(d,2H), 7.25(d,2H), 7.5-7.8 (complex m,5H), 8.0(d,2H), 9.0(d,2H); mass spectrum (positive fast atom bombardment (+ve FAB) DMSO/nitrobenzyl alcohol): 869.4 (2M+H)+ ; microanalysis, found: C,56.7; H,5.3; N,14.9; H2O,8%; C26H22N6O.2HCl.2.5H2O.0.2(C2H5)2O requires C,56.7; H,5.5; N,14.8%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][CH:24]=[N:23][CH:22]=2)=[CH:17][CH:16]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[O:25]1[C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4]3)=[CH:16][CH:17]=2)=[CH:22][N:23]=[CH:24]1
Reactant: Brc1ccc(-c2cnco2)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: FC(F)(F)c1nn(-c2ccc(-c3cnco3)cc2)c2c1CCCC2
Temperature: 180 °C
Yield: 30 %

Procedure:
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg, 0.8 mmol), 5-(4-bromophenyl)-1,3-oxazole (179 mg, 0.8 mmol), N,N-dimethylglycine (16 mg, 0.16 mmol), copper (I) iodide (16 mg, 0.08 mmol), potassium carbonate (235 mg, 1.7 mmol) in dimethylsulfoxide (3 ml) was heated in a microwave reactor at 180° C. for a total of 60 minutes. The reaction mixture was then filtered through a 5 g sep-pack column with 40 ml 1:1 ethyl acetate in petroleum ether. The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was retained and washed with brine (2×10 ml). The organic material was then purified by MDAP. The relevant fractions were combined and the solvent removed by rotary evaporation to give the named products. Product was then partitioned between dichloromethane (40 ml) and water (40 ml). The organic layer was retained and the solvent removed by rotary evaporation to give the title compound (80 mg, 30%).
Reaction SMILES: [C:1]([C:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH:5]([CH:11]=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[C:21]([O:20][C:18]([C:4]1([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:1](=[O:3])[CH:2]=[CH:11][CH:5]1[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(C=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 790 mg quantity of the compound (7) obtained above is dissolved in 50 ml of benzene containing 1 ml of acetic acid and 1 ml of piperidine, and the solution is refluxed for 4 hours. On completion of the reaction, the solvent is removed, and the residue dissolved in ethyl acetate. The solution is washed with water and an aqueous solution of sodium bicarbonate and thereafter dried. The residue is distilled in a vacuum, giving 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (2-a), R1 =t-Bu, R2 =CH3) in a yield of 78%, b.p. 82°-86° C./0.006 mm Hg.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[C:33][CH3:34]>CN(C)C=O.O.[Cl-].[Na+]>[CH2:31]([N:4]1[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=[C:3]1[S:2][CH3:1])[C:32]#[C:33][CH3:34]
Reactant: CC#CCBr
Reactant: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(SC)nc2cnn(Cc3cccc4ccccc34)c(=O)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 900 mg (2.79 mmol) of 2-methylsulphanyl-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (Example 1f) in 15 ml of dimethylformamide was combined with 415 mg (3.0 mmol) of potassium carbonate and 399 mg (3.0 mmol) of 1-bromo-2-butyne and stirred at ambient temperature for eight hours. Then the mixture was diluted with approx. 30 ml of water and saturated with sodium chloride, whereupon the reaction product crystallised out. It was suction filtered and purified by column chromatography (silica gel, eluant:petroleum ether with 10–50% ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:33])[NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([O:31]C)=[O:30])[C:22]=4[N:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:33])[NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])=[O:30])[C:22]=4[N:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2[nH]c(NC(=O)c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3nc4c(C(=O)O)cccc4[nH]3)ccc2C1
Yield: 72.4 %

Procedure:
109 mg (0.242 mmol) of 6-(4-methoxycarbonyl-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester was hydrolyzed using 1 mL of 2 N aq. LiOH, 4 mL of THF and 1 mL of methanol stirring at room temperature for one day as described in general procedure B. 76.5 mg (72%) of the 6-(4-Carboxy-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester product was obtained. LCMS: 437 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([CH3:28])([C:26]#[CH:27])[C:22]([O:24][CH3:25])=[O:23]>>[C:15]([C:13]1[N:14]=[C:7]2[C:6]3[CH:18]=[C:2]([C:27]#[C:26][C:21]([OH:20])([CH3:28])[C:22]([O:24][CH3:25])=[O:23])[C:3]([F:19])=[CH:4][C:5]=3[O:11][CH2:10][CH2:9][N:8]2[CH:12]=1)(=[O:16])[NH2:17]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)C(=O)OC
Product: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with methyl 2-hydroxy-2-methylbut-3-ynoate to give the titled compound as a brown oil. M+1=374
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1
Reactant: OCc1ccc(-c2ccccn2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccn2)s1
Temperature: 25 °C
Yield: 8307.6 %

Procedure:
A solution of (5-(pyridin-2-yl)thien-2-yl) methanol (0.100 g) and manganese dioxide (0.136 g) in tetrahydrofuran (3.5 mL) was refluxed overnight. The mixture was cooled to room temperature and the solids were filtered. The filtrate was concentrated and the residue was triturated (hexane:diethyl ether=1:1) to obtain the title compound (8.22 g) having the following physical data.
Reaction SMILES: [NH:1]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([O:56]CC1C=CC=CC=1)=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[Cl:49])=[O:44])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:67]([O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:68])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([OH:56])=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[Cl:49])=[O:44])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
At 0° C. to the solution of 100 mg (0.95 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 13) in 20 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)-Obzl (SEQ ID NO: 13). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 880 mg (91%) of the title compound as a colorless powder.