Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[N:12]1
Reactant: CC(C)(C)OC(=O)NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
Part B: To a solution of 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.91 gram, 4.8 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (5 ml) and the resulting solution was stirred at room temperature for 5 hours. After concentration in vacuo the residue was dissolved in ethylacetate and washed with 2 N sodium hydroxide solution. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-(2-aminoethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.44 gram, quantitative yield) as an oil.
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Cl-].[K+].OCC(CO)O.[P:29]([O:41][CH2:42][C@H:43]1[O:47][C@@H:46]([N:48]2[C:58]3[N:57]=[C:55]([NH2:56])[NH:54][C:52](=[O:53])[C:51]=3[N:50]=C2)[C@H:45](O)[C@@H:44]1[OH:60])([O:32][P:33]([O:36][P:37]([OH:40])([OH:39])=[O:38])([OH:35])=[O:34])(=[O:31])[OH:30]>C(O)C(N)(CO)CO.Cl>[CH2:46]1[NH:48][C:58]2[NH:57][C:55]([NH2:56])=[N:54][C:52](=[O:53])[C:51]=2[N:50]=[C:45]1[C@H:44]([OH:60])[C@H:43]([OH:47])[CH2:42][O:41][P:29]([O:32][P:33]([O:36][P:37]([OH:40])([OH:39])=[O:38])([OH:35])=[O:34])([OH:30])=[O:31]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: OCC(O)CO
Product: Nc1nc(=O)c2c([nH]1)NCC([C@H](O)[C@H](O)COP(=O)(O)OP(=O)(O)OP(=O)(O)O)=N2

Procedure:
Sephadex G-25 eluates were prepared in 0.1 M Tris-HCl, pH 7.8, 5 mM EDTA, 0.3 M KCl, and 10% (v/v) glycerol. The eluate was incubated with 2 mM GTP for 90 min at 37° C. in the dark. The dihydroneopterin triphosphate formed was oxidized to neopterin triphosphate with 0.1 M HCl, 0.01 M I2 for 1 hour in the dark at room temperature. Precipitate was removed by centrifugation at 10,000×g for 5 min. Excess iodine was reduced by 0.1 M ascorbic acid and the acid neutralized by adding 1 M NaOH. Neopterin was produced by incubation with 8 Units/ml of alkaline phosphatase for 1 hour at 37° C. Neopterin was quantified by reverse-phase HPLC with fluorescence detection.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:28][C:25]([OH:26])([CH3:27])[C:23]([NH:22][C:15]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=1)=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc([N+](=O)[O-])c(F)c2)ccc1[N+](=O)[O-]

Procedure:
3-(3-Fluoro-4-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 3-fluoro-4-nitrophenol and 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. 1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J=10.1 Hz), 4.41 (1H, d, J=10.1 Hz), 6.36 (1H, bs), 6.96 (1H, m), 7.22 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.90 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=9.0 Hz), 8.24 (1H, m), 10.19 (1H, s).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].CN1C=CN=C1.[NH2:25][C:26]1[C:27]2[CH:47]=[CH:46][CH:45]=[CH:44][C:28]=2[C:29]2[CH:30]([CH2:42][Cl:43])[CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:33]=2[CH:34]=1>C(Cl)Cl>[C:38]([O:37][C:35]([N:32]1[C:33]2[CH:34]=[C:26]([NH:25][C:2]([O:4][CH2:5][CH:6]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)=[O:3])[C:27]3[CH:47]=[CH:46][CH:45]=[CH:44][C:28]=3[C:29]=2[CH:30]([CH2:42][Cl:43])[CH2:31]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(N)c1ccccc21
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(NC(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc21
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A solution of 9-fluorenylmethyl chloroformate (97%, 270 mg, 1.01 mmol) in dry CH2Cl2 (20 mL) was treated with 1-methylimidazole (90 mg, 1.10 mmol), followed by the above amine (270 mg, 0.84 mmol). The mixture was stirred at 20° C. for 1.5 h, then treated with additional 1-methylimidazole (18 mg, 0.22 mmol) and 9-fluorenylmethyl chloroformate (54 mg, 0.20 mmol). The mixture was stirred for a further 3 h and was then concentrated under reduced pressure, and the residue was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (9:1) gave a solid that was recrysallized from iPr2O/petroleum ether to give give 3-(tert-butyloxycarbonyl)-1-(chloromethyl)-5-(9-fluorenylmethyloxycarbonylamino)-1,2-dihydro-3H-benz[e]indole (417 mg, 89%), mp 103-106° C. 1H NMR [(CD3)2SO] δ 9.73 (s, 1 H, NHCO2), 8.21 (br s, 1 H, H-4), 7.98 (d, J=8.5 Hz, 1 H, ArH), 7.95-7.85 (m, 3 H, ArH), 7.76 (br s, 2 H, ArH), 7.54 (t, J=7.5 Hz, 1 H, ArH), 7.48-7.27 (m, 5 H, ArH), 4.46 (d, J=7.0 Hz, 2 H, aliphatic H), 4.32 (t, J=6.8 Hz, 1 H, aliphatic H), 4.26-4.11 (m, 2 H, aliphatic H), 4.11-3.97 (m, 2 H, CHHCl, aliphatic H), 3.88 (dd, J=10.7, 6.9 Hz, 1 H, CHHCl), 1.52 (s, 9 H, C(CH3)3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][CH2:37][OH:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][CH2:37][OH:38])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CCO)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromoethanol (0.40 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 23%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][O:9]2)[CH:7]=1.CO.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][OH:15])[CH2:10][O:9]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(C2CSC(COCc3ccccc3)CO2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=O)n(C2CSC(CO)CO2)cc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
5-Fluoro-1-(5-benzyloxymethyl-1,4-oxathian-2-yl)uracil (0.46 g) was dissolved in methylene chloride (50 ml), and the solution cooled to -78° C. To the solution, t-boron trichloride (13.1 ml) was added dropwise, and the mixture stirred at the same temperature for 4 hours. After adding a mixture of methanol-methylene chloride (1/1, 14 ml) and then sodium bicarbonate thereto, the resultant mixture was stirred at room temperature. Upon filtering the mixture to remove solid materials, the filtrate was concentrated, and the residue was purified on a silica gel column chromatography (eluent: chloroform/methanol=15/1) to obtain the desired product (0.11 g) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][C:6]=1[NH:13][C:14]([NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[O:15].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:7][C:6]=1[NH:13][C:14]([NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[O:15]
Reactant: C1COCCN1
Reactant: COc1cccc(F)c1Oc1ccc(C=O)cc1NC(=O)Nc1nccs1
Product: COc1cccc(F)c1Oc1ccc(CN2CCOCC2)cc1NC(=O)Nc1nccs1
Yield: 78 %

Procedure:
1-[2-(2-Fluoro-6-methoxy-phenoxy)-5-morpholin-4-ylmethyl-phenyl]-3-thiazol-2-yl-urea (35 mg, 78%) was prepared from 1-[2-(2-fluoro-6-methoxy-phenoxy)-5-formyl-phenyl]-3-thiazol-2-yl-urea (39 mg, 0.1 mmol) and morpholine following the general procedure O.
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[N:6]([CH3:18])[C:5]1=[O:19])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][CH:4]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[N:6]([CH3:18])[C:5]1=[O:19]
Reactant: CCSC1=NC(N=[N+]=[N-])C(=O)N(C)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCSC1=NC(N)C(=O)N(C)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 1.90 mmol of azide (see Step B above) in 13 mL of tetrahydrofuran to which had been added 1 mL of water is treated with an excess of triphenyphospine (2.8 equivalents) added in one portion as a solid. The reaction is stirred at room temperature under nitrogen cover for twenty hours and then diluted with ethyl acetate. The solution is extracted with 1N HCl three times, and the combined extracts are rendered basic by the addition of 5N NaOH. This is extracted three times with ethyl acetate and the combined extracts washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo on a rotary evaporator at 20° C. The resulting oil is used immediately.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][CH:21]1[CH2:28][CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[N:23]([CH2:33][C:34]([OH:36])=[O:35])[C:22]1=[O:37])[C:17]([OH:19])=[O:18])(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][CH:21]1[CH2:28][CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[N:23]([CH2:33][C:34]([OH:36])=[O:35])[C:22]1=[O:37])[C:17]([OH:19])=[O:18]
Reactant: O=C(O)CN1C(=O)C(N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)O)CCCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: NCCCC[C@H](NC1CCCc2ccccc2N(CC(=O)O)C1=O)C(=O)O

Procedure:
A solution of 3-[(5-carbobenzyloxyamino-1-(S)-carboxypentyl)amino]-1-carboxymethyl-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one (isomer B) (2.1 g) in ethanol (300 ml) is hydrogenated at atmospheric pressure using 5% palladium on charcoal (0.5 g) as catalyst. The catalyst is filtered off and the solvent is removed under reduced pressure to give 3-[(5-amino-1-(S)-carboxypentyl)amino]-1-carboxymethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (Isomer B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[Cl:23][C:24]1[C:25]([CH2:30][NH2:31])=[N:26][N:27]([CH3:29])[CH:28]=1>>[Cl:23][C:24]1[C:25]([CH2:30][NH:31][C:13](=[O:14])[C:12]2[CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=2)=[N:26][N:27]([CH3:29])[CH:28]=1
Reactant: Cn1cc(Cl)c(CN)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cn1cc(Cl)c(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and [(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]amine (CAS Registry No. 1017785-44-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 458.0604 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].SCCO.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.CCCCCC>C(OCC)(=O)C>[C:1]([N:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCCC1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: OCCS
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CC(=O)N1C=CCC1
Reaction time: 7 h
Yield: 95 %

Procedure:
7.5 parts of exemplified compound 1-1, compound represented by Formula (I), and 2.5 parts of N-acryloylpyrrolidine were dissolved in 8 parts of ethyl acetate. 0.033 parts of 2-mercaptoethanol was added to the resultant solution. Polymerization was carried out in the presence of 0.02 parts of 2,2′-azobis(2,4-dimethylvaleronitrile) (V-65™ manufactured by Wako Pure Chemical Industries, Ltd.,) serving as a polymerization initiator at a surrounding temperature of 70° C. for 7 hours under nitrogen flow. After the completion of the polymerization, the resultant polymer solution was added to 100 parts of hexane to precipitate a product. As a result, 9.5 parts of exemplified polymer 2-18 was be produced by radical polymerization of the above-mentioned compound 1-1 and N -acryloylpyrroline (yield: 95%).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](OC)=O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccccn1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccn3)nc(=O)c1-2

Procedure:
Sodium metal (310 mg) was dissolved in ethanol (75 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.1 g, 5 mmol) and methyl 2-pyridinylacetate (1.52 g, 10 mmol) were added. The reaction mixture was heated at reflux for 28 hours, the solvent was removed in vacuo and the residue was dissolved in water (50 ml) and acidified with acetic acid. The mixture was extracted with CHCl3 (100 ml), the solvent was removed and the oily residue was crystallized from cyclohexane to afford 0.85 g of crude product. The product was purified by column chromatography on silica gel eluting with ether, followed by recrystallization from cyclohexane, to afford 1-cyclopentyl-3-ethyl-6-(2-pyridinylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, as yellow crystals, m.p. 120°-122° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[NH:52][C:51]([C:53](O)=[O:54])=[C:50]([Cl:56])[CH:49]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[NH:52][C:51]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])=[C:50]([Cl:56])[CH:49]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Reaction time: 8 h
Yield: 16.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 5-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0127 g, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.29 (s, 3H) 4.48 (d, J=5.36 Hz, 2H) 7.10 (s, 1H) 7.36-7.56 (m, 4H) 7.80 (s, 1H) 8.71 (t, J=5.22 Hz, 1H) 12.31 (br. s., 1H). LCMS: m/z 477.9 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)c1
Yield: 77 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and 3-methoxybenzeneboronic acid resulting in a 77% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:9]=2[C:24]([O:26]C)=[O:25])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([CH:18]([CH3:19])[CH3:20])[N:11]=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9]=2[C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=CO)c1-c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)c1nc(C(C)C)c(C(=O)O)c(-c2ccc(F)cc2)c1CC=CO
Yield: 55.4 %

Procedure:
A solution of 4-(4-Fluorophenyl)-5-(3-hydroxy-2-propenyl)-2,6-bis(1-methylethyl)-3-pyridinecarboxylic acid, methyl ester (7.5 g, 0.0202 mol) and KOH (3.66 g, 0.0652 mol) in n-butanol was refluxed for 72 hours followed by concentration of the butanol under reduced pressure. The residue was partitioned between water (250 ml) and diethylether (100 ml). The aqueous layer was acidified (citric acid) and extracted with chloroform (3×150 ml). The organic layer was dried (MgSO4) and concentrated to yield 4.0 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([CH:42]=2)[C:40]#[N:41])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:35]3[CH:36]=[N:37][CH:38]=[C:39]([C:40]#[N:41])[CH:42]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 179.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=474.3 [M+H]+, m/z=472.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 3.48 (d, J=5.38 Hz, 2H) 3.56 (d, J=5.38 Hz, 2H) 4.66 (br. s, 1H) 7.36 (d, J=9.05 Hz, 2H) 7.81-7.93 (m, 2H) 8.15 (d, J=2.45 Hz, 1H) 8.46 (t, J=2.08 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 9.01 (dd, J=7.21, 2.08 Hz, 2H) 10.23 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]45[CH2:29][CH:24]6[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]6)[CH2:21]4)[CH2:27]5)=[CH:16][CH:15]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]4[O:11][C:7]5[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:31]=[CH:30][C:8]=5[N:9]=4)=[CH:15][CH:16]=3)[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]([CH2:25]3)[CH2:29]1)[CH2:21]2
Reactant: COC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
To a solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester (110 mg, 0.26 mmol) in dimethyl sulfide (10 ml) and dichloromethane (10 ml) was added aluminum bromide (1.13 g, 4.22 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (81.6 mg, 76.8% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[C:6]([O:15][CH3:16])=[N:5]2.ClC1C([C:29](OCC)=[O:30])=NC2C(N=1)=CC(Cl)=CC=2>>[CH3:16][O:15][C:6]1[C:7]([C:12]([OH:14])=[O:13])=[N:8][C:9]2[C:4]([N:5]=1)=[CH:3][C:2]([O:30][CH3:29])=[CH:11][CH:10]=2
Reactant: COc1nc2cc(Cl)ccc2nc1C(=O)O
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2nc1Cl
Product: COc1ccc2nc(C(=O)O)c(OC)nc2c1

Procedure:
In a similar manner, 6-chloro-3-methoxy-2-quinoxalinecarboxylic acid, m.p. 165°-167°, was prepared from 3,6-dichloro-2-quinoxalinecarboxylic acid, ethyl ester (Example 12b) (68%).
Reaction SMILES: [NH2:1][C:2]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)=[O:3].[F:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:7]([C:4]2([C:2]([NH2:1])=[O:3])[CH2:5][CH2:6]2)=[O:9])=[CH:18][CH:17]=1
Reactant: NC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C1(C(=O)Nc2ccc(OCc3cccc(F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A solution of 126 mg (1 mmol) of 1-(aminocarbonyl)-1-cyclopropan-carboxylic acid and of 212 mg (1 mmol) 4-(3-fluoro-benzyloxy)-phenylamine (prepared as in example 1b) in 10 ml dichloromethane is cooled to 0° C. and treated with 206 mg (1.1 mmol) N-(−3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride (EDCI). The mixture is stirred for additional 2 h at room temperature, evaporated and acidified with dil. citric acid. Extraction with ethyl acetate and recrystallisation from methanol yields 178 mg (56%) of the title compound. Yellowish solid; MS: m/e=329.3 (M++H).
Reaction SMILES: [CH:1](=[C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]C(Br)(Br)Br>C(#N)C>[Br:32][CH2:11][CH2:10][CH:7]1[CH2:8][CH2:9][C:4](=[CH:1][CH2:2][CH3:3])[CH2:5][CH2:6]1
Reactant: CCC=C1CCC(CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCC=C1CCC(CCBr)CC1

Procedure:
40.4 g of 2-(4-propylidenecyclohexyl)ethanol, 69.5 g of triphenylphosphine and 500 ml of acetonitrile were cooled to -5° C. A solution of 99.5 g of tetrabromomethane in 100 ml of acetonitrile was then added with stirring, and the mixture was stirred at RT overnight. The solvent was then removed, and the residue was subjected to conventional work-up, giving 1-(2-bromo-ethyl)-4-propylidenecyclohexane.