Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15](=[CH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:16]([O:18][CH3:19])=[O:17])(=O)[CH3:13]>>[CH:21]1([CH:20]2[N:8]3[CH:9]=[CH:10][N:11]=[C:7]3[NH:6][C:12]([CH3:13])=[C:15]2[C:16]([O:18][CH3:19])=[O:17])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1ncc[nH]1
Reactant: COC(=O)C(=CC1CCCCC1)C(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1=C(C)Nc2nccn2C1C1CCCCC1

Procedure:
Crystals are obtained by reacting 6.8 of 2-aminoimidazole sulfate with 10.5 g of methyl 2-acetyl-3-cyclohexylacrylate in a similar manner as described in Example 13. Recrystallization from methanol gives 4.8 g of 5-cyclohexyl-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 178° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14](OCC)[O:15]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14]=[O:15]
Reactant: CCOC(C#CCCCCCCCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=CC#CCCCCCCCCCCCl
Temperature: 62.5 °C
Yield: 87 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 13-chloro-1,1-diethoxy-2-tridecyne (302.9 g:1.0 mol), para-toluenesulfonic acid (8.0 g:0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and then stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 13-chloro-2-tridecynal [bp: 116-122° C./0.13 KPa, 198.6 g, 0.87 mol]. [Yield: 86.8%]
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([CH2:19][C@H:20]4[CH2:22][C@@H:21]4[CH3:23])[C:13]=23)=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O.[C:49]([OH:52])(=[O:51])[CH3:50]>>[C:49]([O:52][CH2:17][C:16]1[C:12]2[C:13](=[C:8]([O:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[N:10][CH:11]=2)[N:14]([CH2:19][C@H:20]2[CH2:22][C@@H:21]2[CH3:23])[C:15]=1[CH3:18])(=[O:51])[CH3:50]
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Reactant: CC(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CC(=O)OCc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (0.679 g, 2.00 mmol) in acetic acid (40 ml) was added ammonium cerium (IV) nitrate (6.58 g, 12.0 mmol) at room temperature. The mixture was stirred at 60° C. for 3 hours, poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using hexane/ethyl acetate=1/1 as the eluant to afford an oil which was crystallized in hexane to give the title compound (0.255 g, 28%) as pale yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:24])(=O)=O)=CC=1.Cl>C1COCC1.C(OCC)C>[F:24][C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccs1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1sccc1F
Temperature: -78 °C
Yield: 40 %

Procedure:
2-Thiophene-carboxylic acid (1.7 g, 13.3 mmol) was dissolved in anhydrous THF (30 mL) and the solution was cooled to −78° C. under Ar, with stirring. n-Butyllithium (18.3 mL, 29.3 mmol) in hexanes was added to the above solution and the mixture was stirred for 30 min. A solution of N-fluorobenzenesulfonimide (5 g, 15.9 mmol) in THF (30 mL) was then added and the resulting solution was stirred at −78° C. for 4 h and allowed to warm to ambient temperature over a period of 6 h. The reaction was diluted with diethyl ether (100 mL), cooled to 0° C., and 1 N HCl (15 mL) was added to give a biphasic mixture. The aqueous layer was isolated and washed with diethyl ether (3×50 mL). The combined ethereal layers were dried over MgSO4, filtered, and concentrated in vacuo to yield an orange oil. The oil was subjected to column chromatography on silica gel using 1:1 hexanes/ethyl acetate as the eluent. (14) was obtained as a slightly brown solid (0.777 g) in 40% yield. TLC (1:1 ethyl acetate/hexanes) Rf 0.17; 1H NMR (CDCl3) δ 10.7 (s, 1H), 7.53 (dd, J=5.4, 3.6 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2 (d, J=3.5 Hz), 161.5 (d, J=278 Hz), 132.0 (d, J=10 Hz), 118.9 (d, J=24.7 Hz), 113.6; 19FNMR (282 MHz, CDCl3, CFCl3) δ-65.2 (d, J=6 Hz); EI-MS m/e 145.9838 (M+ calcd 145.9838 for C5H3FO2S).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:32]=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].Cl.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([CH:3]1[C:4]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]=[C:15]([C:17]4[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]5[CH2:24][CH2:25][N:26]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:27][CH2:28]5)=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=2)=[N:5][NH:6][C:7](=[O:9])[CH2:8]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC4CCNCC4)cc3)oc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC4CCN(S(C)(=O)=O)CC4)cc3)oc2c1

Procedure:
15.5 mg (33 μmol) 4-{4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxymethyl}-piperidine as hydrochloride are stirred together with 2.6 μl (34 μmol) methanesulphonic acid chloride, 14 μl (100 μmol) triethylamine and 2 ml DCM at RT overnight within the next 4 days a further 14.4 μl methanesulphonic acid chloride and 24.5 μl triethylamine are added batchwise. Then the reaction mixture is combined with DCM and extracted 2× with 25 ml of water+3 drops of glacial acetic acid, 5% sodium carbonate solution and sat. saline solution. The solv. of the org. phase is evaporated off completely i.V. and the residue is stirred with cyclohexane/EA.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:12]([OH:13])[CH2:14][OH:15])[CH3:2]
Reactant: OCC1CO1
Reactant: CCOc1ccccc1O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOc1ccccc1OCC(O)CO
Yield: 65.6 %

Procedure:
A solution of 41.5 g (0.3 mole) of 2-ethoxyphenol, 29.6 g (0.4 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux temperature for 18 hr. The mixture was concentrated to a thick oil that crystallized slowly over several days. The crude product was chromatographed on a silica gel column (1.2 kg) using increasing portions of acetone in methylene chloride to elute the product. The desired fractions were combined and concentrated to give a yellow oil that crystallized on standing. The solid was triturated with petroleum ether and the mixture filtered to obtain 41.8 g of solid. Recrystallization from carbon tetrachloride yielded 37.2 g (58%) of white solid, mp 64°-65° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[O:10]1[C:14]2[CH:15]=[C:16]([C:19]([NH:21][C@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23](O)=[O:24])=[O:20])[CH:17]=[CH:18][C:13]=2[O:12][CH2:11]1>>[CH3:28][CH:27]([CH3:29])[CH2:26][C@@H:22]([NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][O:10][C:14]=2[CH:15]=1)=[O:20])[C:23](=[O:24])[NH:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1cccnc1
Reactant: CC(C)C[C@@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)O
Product: CC(C)C[C@@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)NCCc1cccnc1

Procedure:
Prepared in a similar manner to example 13 using 2-(3-pyridyl)ethylamine and (R)-2-(benzo[d][1,3]dioxole-6-carboxamido)-4-methylpentanoic acid (example 13a). (MS M+384.2).
Reaction SMILES: C([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:20])=[O:5])=[O:19])(=[O:18])[CH3:17]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(3-Acetylthiopropanoyl)-L-proline-t-butyl ester (4.7 g.) is dissolved in a mixture of anisole (34 ml.) and trifluoroacetic acid (68 ml.) and the mixture is kept at room temperature for 1 hour. The solvents are removed in vacuo and the residue is precipitated from ether-hexane several times. The residue (3.5 g.) is dissolved in acetonitrile (25 ml.) and dicyclohexylamine (2.8 ml.) is added. The crystalline salt is filtered and recrystallized from isopropanol. Yield 3.8 g.. m.p. 176°-177°. The salt is reconverted to 1-(3-acetylthiopropanoyl)-L-proline as in Example 1, yield 1.25 g., m.p. 89°-90° (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Br)cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@:5]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:10])[F:9])[CH:4]=[CH:3]1.[H][H]>[Pd].CO>[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@@:5]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:9])[F:10])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)C=C[C@@H](N)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)CC[C@@H](N)C1

Procedure:
A mixture of tert-butyl (1S,4S)-5-{[(1S,4S)-4-amino-1-(2,2-difluoroethyl)cyclopent-2-en-1-yl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6.50 g, 17.5 mmol) and 5% palladium on carbon in methanol (100 ml) was stirred at room temperature under 46 psi of hydrogen for 21 hours. The reaction was filtered through celite and the filter cake washed with methanol. The filtrate and washings were concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-(2,2-difluoroethyl)cyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a brown oil (6.67 g, theoretical yield 6.54 g) which was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][N:10]=2)[N:7]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][OH:12])=[N:9][N:10]=3)[N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1nnc2ccc(-c3ccccc3)nn12
Temperature: 85 °C

Procedure:
A suspension of (6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.289 mmol, 1 eq), phenylboronic acid (0.665 mmol, 2.3 eq), Pd(PPh3)4 (45.9 mg, 0.0405 mmol, 14 mol %), and K2CO3 (132 mg, 0.955 mmol, 3.3 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated conventionally at 85° C. for 1 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by pTLC [Silicycle, 1000 μM, 20×20 plate], which required two developments in a 3% MeOH in EtOAc solvent system. 1H NMR (400 MHz, CDCl3): δ=1.69 (br s, 1H), 5.35 (s, 2H), 7.56-7.60 (m, 3H), 7.64 (d, J=9.6 Hz, 1H), 7.97-8.02 (m, 2H), 8.22 (d, J=9.6 Hz, 1H). MS (ES+): m/z 227.08 (100) [MH+]. HPLC: tR=2.42 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Product: FC(F)(F)COc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 68.7 %

Procedure:
Reaction of 1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (174 mg, 69%). MS (ISP) 507.5 [(M+H)+]; mp 181° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:10])=[CH:5][CH:4]=1.I.CS[C:31]1[NH:32][CH2:33][CH2:34][N:35]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]3[NH:35][CH2:34][CH2:33][N:32]=3)=[CH:8][CH:7]=2)=[O:10])=[O:27])=[N:21][CH:22]=1
Reactant: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CSC1=NCCN1
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(CNC2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (80 mg, 0.21 mmol), 2-methylthio-2-imidazoline hydriodide (77 mg, 0.315 mmol, 1.5 equiv.) and triethyl amine (0.5 mL) in 1 mL DMF was stirred at room temperature overnight, concentrated to dryness and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[(2-imidazolin-2-ylamino)methyl]phenyl}carboxamide (13.5 mg, 15%). MS found for C23H21ClN6O2 (M+H)+: 449
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].[F:15][C:16]([F:27])([F:26])[C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC>CN(C=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:17]([C:16]([F:26])([F:27])[F:15])[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]2[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Reactant: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A yellow solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (1.32 g, 4.94 mmol, Intermediate 8, step b) and 1,1,1-trifluoro-3-phenylpropan-2-one (0.980 g, 5.21 mmol) in DMF (4.95 mL) was treated with tributylamine (1.23 mL, 5.19 mmol) and stirred at 130° C. under air (capped) for 2 hours. The homogeneous orange solution was then cooled to room temperature and partitioned with ether (8 mL) and 1 M NaH2PO4 (8 mL). The organic layer was washed with 1 M NaH2PO4 (1×8 mL), dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a heptane to 30% DCM/heptane gradient to yield the title compound as a nearly colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[NH:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#CCC(=O)c1cccc(Br)c1
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Br)c2)n[nH]1
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
A mixture of 3-(3-bromophenyl)-3-oxopropanenitrile (35 g, 156 mmol) and hydrazine hydrate (11.34 mL, 234 mmol) in ethanol (600 mL) was refluxed for 16 h. Mixture was then cooled and concentrated in vacuuo. Crude product was diluted with dichloromethane and stirred for 5 min. Solids were filtered and dried to afford 3-(3-bromophenyl)-1H-pyrazol-5-amine (30 g, 126 mmol, 81% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br. s., 0.4H), 11.66 (br. s., 0.6H), 7.86 (t, J=1.6 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.45 (d, J=6.8 Hz, 1H), 7.37-7.18 (m, 1H), 5.78 (br. s., 1H), 5.08 (br. s., 1.2H), 4.68 (br. s., 0.8H). LCMS (M+H)=240.1.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1ccc(CBr)cc1F
Solvent: O
Product: Nc1cc(O)nc(SCc2ccc(F)c(F)c2)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (2.0 g) with 3,4-difluorobenzyl bromide (2.66 g) to afford the subtitle compound as a white solid. Yield: 3.35 g.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[CH3:10]>N1CCCCC1>[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH2:15][CH2:16][CH3:17])[CH3:10]
Reactant: CCCC(C)=CC(=O)OCC
Reactant: SCc1ccccc1
Solvent: C1CCNCC1
Product: CCCC(C)(CC(=O)OCC)SCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 62.1 g (0.5 mol) of benzyl mercaptan and 78.1 g (0.5 mol) of (rac)-3-methyl-2-hexenoic acid ethyl ester of step (a) in 100 ml of piperidine was heated at reflux until complete reaction was observed (48 h), and cooled to room temperature. Then the excess of piperidine was distilled off at reduced pressure (0.04 mbar, 26-33° C.). The residue, 96.5 g (68%) of (rac)-3-benzylsulfanyl-3-methyl-hexanoic acid ethyl ester, was of good purity and was directly used in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:17]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:28][CH:20]([C:19]([O:18][CH2:16][CH3:17])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: CCOC(=O)C(N)Cc1ccccn1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: CCOC(=O)C(Cc1ccccn1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-2-yl-propionic acid ethyl ester to provide after chromatographical separation the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])=[CH:6][C:5]=1[C:13]([F:14])([F:16])[F:15]
Reactant: COC(=O)c1cc(OC)c(N)cc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirred solution of 5-methoxy-4-amino-2-trifluoromethyl-benzoic acid methyl ester (552 mg, 2.22 mmol) in 6.6 mL CH2Cl2 at 0° C. under nitrogen was added pyridine (180 μL, 2.22 mmol) followed p-nitrophenyl chloroformate (448 mg, 2.22 mmol) as a solid. After stirring for 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 2N HCl and 1×30 mL with H2O. The organics were dried (MgSO4), filtered and concentrated to the p-nitrophenyl carbamate which was isolated as a white foam (878 mg, 96%). 1H-NMR (400 MHz, CDCl3) δ 8.57 (br s, 1H), 8.30 (d, 2H), 7.77 (br s, 1H), 7.40 (d, 2H), 7.37 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[O:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([C@H:34]3[CH2:35][CH2:36][O:32][CH2:33]3)[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1CCOC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN([C@H]4CCOC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and dihydrofuran-3(2H)-one were reacted to give the racemic mixture. The enantiomers were separated by SFC to give 572. LCMS m/z: 245.2 (2M+H+)