Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6](=[O:20])[N:7]2NC(OC(C)(C)C)=O.O.[NH2:28][NH2:29]>O1CCOCC1>[NH:28]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6](=[O:20])[NH:7]2)[NH2:29]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nn1c(=O)c(-c2ccccc2)cc2c(Cl)nccc21
Solvent: O
Solvent: C1COCCO1
Product: NNc1nccc2[nH]c(=O)c(-c3ccccc3)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 5-chloro-2-oxo-3-phenyl-1,6-naphthyridine-1(2H)-carbamate (2-2) (2.0 g, 5.6 mmol) and hydrazine hydrate (7.2 g, 112 mmol) in 1,4-dioxane (28 mL) was heated under microwave irradiation at 120° C. for 20 minutes. The solvent was removed under reduced pressure, and water was added to the residue. The resulting solid was collected by filtration to give 5-hydrazino-3-phenyl-1,6-naphthyridine-2(1H)-one (2-3) as a colorless solid.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].N[C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:14].[Cl-:28].[Na+].Cl>O>[Cl:28][C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:14]
Reactant: Nc1ccccc1C(=O)c1ccccc1C(=O)O
Reactant: [Cl-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccccc1Cl
Temperature: 0 °C

Procedure:
To 250 ml. of concentrated sulfuric acid was added, with stirring and slight cooling, 37.5 g. (0.545 mole) of sodium nitrite. To this was added 120.5 g. (0.50 mole) of 2-(2-aminobenzoyl)benzoic acid at such a rate that the temperature of the reaction mixture remained between 30°-40°. After the addition was complete the reaction mixture was stirred for one hour and then poured into one liter of ice and water and filtered. The filtrate was added rapidly to a stirred solution of 55 g. (0.555 mole) of cuprous chloride, 150 g. of sodium chloride, 250 ml. of concentrated hydrochloric acid and 300 ml. of water. The precipitated gum was extracted with chloroform and the extracts were washed twice with water, dried over anhydrous sodium sulfate and evaporated under vacuo to leave a red oil which crystallized upon scratching. Recrystallization from 200 ml. of ethyl acetate gave 2-(2-chlorobenzoyl)benzoic acid as a pink solid. A sample recrystallized three times from ethyl acetate gave colorless prisms, double m.p. 112°-116° and 124°-126°.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:40]>CO>[ClH:40].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36]([F:37])([F:38])[F:39])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.2 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.) conc. hydrochloric acid (0.33 g.) and methanol (10 ml.) was stirred at room temperature for 4 hours. The precipitates were collected by filtration and washed with diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 0.6 g.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:48][C:49]1[O:53][C:52]([CH:54]=O)=[CH:51][CH:50]=1>CCO>[CH3:22][N:7]1[C:6]2=[C:5]3[N:4]([C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:11]2[C:10](=[O:19])[N:9]([CH3:20])[C:8]1=[O:21])[CH2:3][CH2:2][O:1][CH:54]3[C:52]1[O:53][C:49]([CH3:48])=[CH:50][CH:51]=1
Reactant: Cc1ccc(C=O)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCO)cc2n(C)c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCO
Product: Cc1ccc(C2OCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
6-(2-Hydroxyethyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Int C) (244 mg, 0.815 mmol), bismuth triflate (50.9 mg, 0.082 mmol, 10 mol %) and EtOH (2.4 mL) were treated with 5-methylfuran-2-carbaldehyde (commercially available, 0.089 mL, 0.082 mmol). The mixture was heated to 100° C. for 10 min using microwave irradiation. A further portion of 5-methylfuran-2-carbaldehyde (25 μL) was added to the reaction mixture and heating continued at 100° C. for 5 min. A solid formed on cooling, which was collected by reduced pressure filtration and washed with EtOH followed by diethyl ether, affording the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:38]([CH3:40])[CH3:39])[C:12]([C:14]1[NH:15][C:16]([CH2:29][C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])=[N:17][C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:38]([CH3:40])[CH3:39])[C:12]([C:14]1[NH:15][C:16]([CH2:29][C:30]2[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=2[Cl:36])=[N:17][C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
5-Benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (63) (0.17 g, 281 μmol, Eq: 1.00) was dissolved in tetrahydrofuran (1 ml). HCl (211 μl, 422 μmol, Eq: 1.5) was added and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was mostly removed. The residue was partitioned between ethyl acetate and 1M NaOH. The aqueous layer was washed with ethyl acetate, the organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated. The remaining oil was triturated and concentrated several times with ether/hexanes to afford 5-benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (64) (0.113 g, 230 μmol, 82.0% yield) as a white solid.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[K+].[Br-:11].N([O-])=O.[Na+]>OS(O)(=O)=O.O>[Br:11][C@H:2]([CH2:3][C:4](=[O:6])[NH2:5])[C:7]([OH:9])=[O:8]
Reactant: [Br-]
Reactant: NC(=O)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NC(=O)C[C@@H](Br)C(=O)O
Yield: 78.1 %

Procedure:
D-Asparagine 1 (195.0 g, 1.299 mol) and KBr (461 g, 3.87 mol) were dissolved in 3M H2SO4 (1720 ml). The solution was cooled in an ice-MeOH bath and stirred while a solution of NaNO2 (111.5 g. 1.62 mol) in H2O (200 ml) was added dropwise over 85 minutes. The temperature of the reaction mixture was kept at -5° during the addition and for an additional 60 minutes. The white precipitate was collected, washed twice with ice-cold water, and dried i.v. to give the bromo derivative 2 (198.9 g, 78%): [α]D +69.0° (C., 4.63, EtOH). ##STR82##
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[NH:10][C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.[Br:16][C:17]1[C:21]2[CH:22]=[C:23]([CH2:26]Br)[CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].O>CN(C=O)C>[Br:16][C:17]1[C:21]2[CH:22]=[C:23]([CH2:26][N:10]3[C:8]4=[N:9][C:4]([CH3:3])=[CH:5][C:6]([CH3:15])=[C:7]4[N:12]=[C:11]3[CH2:13][CH3:14])[CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1oc2ccc(CBr)cc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2oc(-c3ccccc3NC(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 25 °C

Procedure:
Sodium hydride (0.2 g) was added in portions over 5 min to a mixture of 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (described in EP-A-0400974) (1.0 g) in dry DMF (25 ml) and stirred at room temperature under nitrogen. After 30 min the solution was cooled to 0°-5° C. and 1,1-dimethylethyl [2-[3-bromo-5-(bromomethyl)-2-benzofuranyl]phenyl]carbamate (described in European Patent Specification No. 0 434 249 A, published 26th Jun. 1991) (3.45 g) was added portionwise over 5 min. The mixture was allowed to warm to room temperature and was stirred for 18 h. Water (1 ml) was added and the mixture concentrated in vacuo. Dichloromethane (50 ml) was added and the mixture washed with water (100 ml), dried and concentrated in vacuo. The residue was purified by flash column chromatogrpahy eluting with System D (10:1) to give the title compound (2.0 g) as a colourless foam.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[S:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>C(O)(=O)C.ClCCCl>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[S:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:41])[CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCNCC3)c2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (3 drops) was added to a mixture of N-cyclopropyl-3-[2-(cyclopropylmethyl)-1-oxo-4-(piperazin-1-ylsulfonyl)-1,2-dihydroisoquinolin-6-yl]-5-fluoro-4-methylbenzamide (Example 47d, 0.047 g) and paraformaldehyde (7.9 mg) in 1,2-dichloroethane (1 mL). The mixture was stirred at room temperature overnight then sodium triacetoxyborohydride (18.5 mg) was added and the reaction stirred at room temperature for 1 h. DCM (10 mL) was added and the solution washed with water (3×10 mL). The organics were dried (MgSO4), filtered and concentrated under reduced pressure then purified by preparative HPLC (Xbridge column using a 95-5% gradient of aqueous trifluoroacetic acid in acetonitrile) then evaporated to dryness. The product was passed through an ion exchange column (StratoSpheres TM SPE PL-HCO3 MP SPE by Polymer Laboratories, eluting with methanol), to give, after triturating with diethyl ether, the title compound (0.032 g) as a white solid.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Agent: Cl
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c3ccccc3n2)c1
Yield: 17 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 47 (17% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.67 and 2.90 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.74-3.88 (4s, 6H), 4.39 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.15-7.18 (m, 1H), 7.46-7.53 (m, 1H), 7.77-8.19 (m, 6H), 8.68-8.72 (2s, 1H); MS (ESI) m/z 442 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]>C(O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:2]3([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:11][C:10](=[O:12])[C:3]=2[CH:4]=1
Reactant: COc1ccc(O)c(C(C)=O)c1
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Yield: 182.7 %

Procedure:
A solution of (2'-hydroxy-5'methoxyphenyl)ethanone (3.32 g, 20 mmol) and cyclohexanonepyrrolidine (enamine form) (3.18 g, 21 mmol) in dry ethanol (40 ml) is heated to reflux for 1.5 hours under nitrogen gas. The solvent is removed by distillation, and the residue is dissolved in diethyl ether, washed with dilute HCl and then water, dried, and concentrated. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and hexane (1:2) to obtain the title compound as thick syrup (4.5 g, yield 91.3%). ##STR8##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[NH:11][C:12]1[CH:17]=[C:16]([Br:18])[N:15]=[C:14]([Br:19])[C:13]=1[N+:20]([O-:22])=[O:21])[CH3:8].Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].[I-].[Na+]>CC(C)=O>[CH2:7]([O:9][C:10](=[O:23])[N:11]([CH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:28]([C:29]#[N:30])[CH:27]=1)[C:12]1[CH:17]=[C:16]([Br:18])[N:15]=[C:14]([Br:19])[C:13]=1[N+:20]([O-:22])=[O:21])[CH3:8]
Reactant: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: N#Cc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(Br)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 68 using potassium carbonate (1.50 g), (2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (2.0 g) in acetone (40 ml), 3-chloromethyl-benzonitrile (0.82 g) and sodium iodide (0.98 g). This gave the product (2.62 g) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:19]2[C:20]3[S:21][C:13]([CH2:12][N:9]4[CH2:10][CH2:11][N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:5])=[O:4])[CH2:7][CH2:8]4)=[CH:14][C:15]=3[N:16]=[C:17]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:18]=2)[CH2:23][CH2:24]1
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-sulfonic acid dimethylamide (Example 28) was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica yielded 112. NMR (CDCl3): 2.51-2.55 (4H, m CH2), 2.75 (6H, s, Me), 3.22-3.25 (4H, m, CH2), 3.77 (2H, s, CH2), 3.78-3.82 (4H, m, CH2), 3.94-3.97 (4H, m, CH2), 5.14 (2H, br s, NH2), 7.20 (1H, s, Ar) and 9.20 (2H, s, Ar). MS: (ESI+): MH+=520.34.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][C:16]#[C:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3].CS(C(CC#CC1(O)CCCCC1)CCCCCCC(O)=O)(=O)=O>>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Agent: CS(=O)(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC1(O)CCCCC1

Procedure:
The synthesis of this compound is carried out by the hydrogenation process described in Example 15 except that 8-methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid is replaced by an equivalent quantity of 8-methylsulfonyl-11-(1-hydroxycyclohexyl)-10-undecynoic acid (Example 19).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:18]1[CH:23]=[CH:22][C:21]([O:24][C:25](OC2C=CC=CC=2)=[N:26][C:27]#[N:28])=[CH:20][CH:19]=1>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25](=[N:26][C:27]#[N:28])[O:24][C:21]4[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (798 mg, 3.22 mmol) and diphenyl cyanocarbonimidate (853 mg, 3.58 mmol) in THF (10 mL) are stirred at room temp. for 15 h. The reaction mixture is diluted with ether, and the precipitate is filtered off to yield the title product as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:18]=NC=N3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=C([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:18]3[CH:27]=[C:26]([O:25][CH3:24])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C)n2nc(-c3ccc(Br)cc3)nc(-n3cncn3)c12
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 4.0 g (10.80 mmol) of 2-(4-bromophenyl)-5,7-dimethyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine from example 13A in DMF is treated with 2.97 g (16.21 mmol) of 3,4,5-trimethoxyaniline and 2.24 g (16.21 mmol) of potassium carbonate. The reaction mixture is stirred overnight at 90° C. After cooling, the solvent is removed on a rotary evaporator, the residue is treated twice more with toluene and the toluene is stripped off again. The crude product is extracted by stirring with a little methanol and filtered off with suction.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:13]1[C:18](Br)=[CH:17][CH:16]=[C:15]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26]([C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1)#[CH:27].C(N(CC)CC)C>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.C(OCC)(=O)C>[CH2:6]([C:13]1[C:18]([C:27]#[C:26][C:28]2([OH:36])[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:17][CH:16]=[C:15]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOCCOc1ccc(Br)c(Cc2ccccc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOCCOc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
7 ml of N,N-dimethylformamide was added to a mixture of 2-benzyl-3-bromo-6-(2-ethoxyethyl)oxypyridine, 601 mg of 3-ethynyl-3-quinuclidinol, 406 mg of tetrakis(triphenylphosphine)palladium(0), 220 mg of cuprous iodide and 1.7 ml of triethylamine, followed by heating under stirring at 80° C. in an oil bath for one hour in a nitrogen atmosphere. After cooling as it was, ethyl acetate was added thereto. The mixture was filtered through Celite, and it was washed with aqueous ammonia. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using ethyl acetate/hexane as an eluent for separation and purification, to give 247 mg of the target compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[O:24][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:27]=1>>[C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]([C:27]3[CH:26]=[CH:25][O:24][C:23]=3[CH3:22])=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: COC(=O)c1cc(Br)ccc1CS(=O)(=O)c1ccccc1
Product: COC(=O)c1cc(-c2ccoc2C)ccc1CS(=O)(=O)c1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Example 36, starting from methyl 2-(benzenesulphonylmethyl)-5-bromobenzoate (Intermediate 63) and 2-methylfuran-5-boronic acid pinacol ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([OH:12])[CH:9]=[N:8]1.[C:15]([O-])([O-])=O.[Cs+].[Cs+].CI>O1CCCC1>[CH3:15][O:12][C:10]1[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=1
Reactant: C[Si](C)(C)CCOCn1cc(O)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (compound 280.2, 2.14 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added Cs2CO3 (6.5 g, 20.0 mmol) in portions. To this was added CH3I (1.25 mL, 20.0 mmol) dropwise. The reaction mixture was stirred for 3 h at room temperature, then concentrated under reduced pressure. The resulting residue was dissolved in 100 mL of EtOAc. The solids were filtered off and the filtrate was concentrated under reduced pressure. This resulted in 2.1 g (92%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)CCCCCCCCCCC.[Na+].O>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:13])[CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CC(=O)c1ccc(C(N)=O)c(C)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(N)=O
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 85.5 %

Procedure:
0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.96 g of distilled water, 83 mg of potassium carbonate and 13 mg of sodium laurate were fed and the mixture was stirred for 5.5 hours at 70° C. The mixture was left to cool to room temperature and the slurry-state reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of distilled water. 0.71 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide as a flesh color solid was obtained by drying under reduced pressure.