Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH2:10][C:11]([CH3:13])=[CH2:12])[C:3]=1[OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[CH2:10][C:4]2[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=2[O:14]1
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(C)C2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (13.0 g, 68.3 mmol) synthesized in Reference Example 2, p-toluenesulfonic acid monohydrate (1.30 g, 6.83 mmol) and toluene (130 mL) was stirred under heated reflux for 1.5 hours. After cooled to room temperature, the reaction solution was distributed by addition of 1N sodium hydroxide aqueous solution. The organic layer was washed with 1N sodium hydroxide aqueous solution and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by basic silica gel chromatography (hexane-ethyl acetate 49:1 to 24:1) to give 11.1 g of the title compound (yield: 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].OO.C([O-])([O-])=[O:13].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([NH2:6])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(Br)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of m-bromobenzonitrile (2 g, 10 mol) in DMSO (6 mL) was added 30% H2O2 (5 g, 13 mmol) and K2CO3 at 0° C., and stirred at room temperature for 30 min. The mixture was poured into water and filtered, the solid was washed with water, dried to got the compound 0601-142 (1.8 g, 82%) as a white solid. LCMS: 200 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.41 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J1,2=8.0, 0.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.03 (t, J=1.6 Hz, 1H), 8.06 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][C:6]([O:13][OH:14])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].S(=O)(=O)(O)O>CCCCC>[C:2]([O:3][O:13][C:6]([O:14][O:13][C:6]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:12])[CH3:5])([CH3:12])[CH3:5])([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])[CH3:1]
Reactant: CC(C)(C)CC(C)(C)OO
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CC(C)(C)CC(C)(C)OOC(C)(C)OOC(C)(C)CC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
To a jacketed reactor was charged 7.0g. (0.12 mole) of acetone, 39.2g. (0.24 mole) of 1,1,3,3-tetramethylbutyl hydroperoxide (89.7% assay) and 120 ml. of pentane. To the vigorously stirred solution at 0°C was added 16g. of 77% sulfuric acid over a period of 30 minutes and the reaction mixture was allowed to stir at 0°C for 4 hours. The pentane layer was then separated, washed with water, then aqueous 10% KOH solution and finally with water to neutral and was dried over anhyd. MgSO4. After separation of the desiccant and vacuum stripping, 21.3g. (53.1% of theory, uncorr.) of liquid remained which had an "active oxygen" content of 8.66% (theory, 9.64%). Hence, the assay was 90% and the corrected yield was 47.8%. An infrared spectrum of the product showed no O--H or C=O bands but showed a strong OO band at 860 cm-1.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C:17](=O)[C:16](=[O:19])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[NH:21][NH2:22].Cl.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:25]([O:24][C:20]([NH:21]/[N:22]=[C:17]1/[C@H:5]2[S:4][CH2:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16]/1=[O:19])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)/C(=N\NC(=O)OC(C)(C)C)[C@H]2SC1
Yield: 25.6 %

Procedure:
In chloroform (70 ml) are dissolved 2,2,2-trichloroethyl 3-methyl-7-oxo-3-cephem-4-carboxylate (14.30 g), t-butyl carbazate (6.00 g) and pyridine hydrochloride (4.77 g) and the mixture is refluxed in a Dean-Stark trap packed with Molecular Sieve 3A for 30 minutes. The reaction mixture is washed with 1 N-HCl and water in that order, dried over magnesium sulfate and concentrated. The residual oil is subjected to silica gel (240 g) column chromatography and elution is carried out with ethyl acetate-benzene to give crystals of 2,2,2-trichloroethyl (E)-7-t-butoxycarbonylhydrazono-3-methyl-3-cephem-4-carboxylate (4.88 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[CH2:33])[CH2:5][CH:6]([C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:30]([CH3:31])=[N:29][CH:28]=[N:27]3)=[C:22]([F:32])[CH:21]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:32][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[CH2:5][C:4](=[CH2:33])[CH2:3][CH2:2][N:18]3[N:17]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[C:30]([CH3:31])=[N:29][CH:28]=[N:27]1
Reactant: C=C(CCCl)CC(c1ccc(F)cc1)c1nc(Nc2ccc(-n3ncnc3C)c(F)c2)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C1CCn2nc(Nc3ccc(-n4ncnc4C)c(F)c3)nc2C(c2ccc(F)cc2)C1
Yield: 65.1 %

Procedure:
A solution of 5-(5-chloro-1-(4-fluorophenyl)-3-methylenepentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (3.33 g, 7.09 mmol), sodium iodide (5.31 g, 35.4 mmol), and diisoproplylethylamine (2.48 mL, 14.2 mmol) in acetone (50 mL) was heated in a sealed vessel at 100° C. for 1 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50-100% EtOAc/chloroform). The fractions containing product were combined and concentrated to afford N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (2.0 g, 52% yield). LC-MS (M+H)+ 434.1.
Reaction SMILES: [Cl:1]C1C=CC=C2C=1NC=C2C=O.[C:13]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](Cl)[CH:23]=2)[N:18]([CH2:26][C:27]([OH:29])=[O:28])[CH:17]=1)(=[O:15])[NH2:14]>>[C:13]([C:16]1[C:24]2[C:19](=[C:20]([Cl:1])[CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:26][C:27]([OH:29])=[O:28])[CH:17]=1)(=[O:15])[NH2:14]
Reactant: O=Cc1c[nH]c2c(Cl)cccc12
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Product: NC(=O)c1cn(CC(=O)O)c2c(Cl)cccc12

Procedure:
was prepared from 7-chloro-1H-indole-3-carbaldehyde [1008-07-7] using similar protocols as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 253 [M+H]+, 505 [2M+H]+; tR (HPLC conditions b): 3.32 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](N)=[O:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.Cl.[O:29]1CCOCC1>[OH-].[Na+]>[NH2:1][C:2]1[C:3]([C:25]([OH:29])=[O:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:23])[CH3:24])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccc(F)cc2)ccc1=O
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccc(F)cc2)ccc1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3-Amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (30 g) was suspended in dioxane (60 ml) and 2N aq. NaOH (600 ml). The mixture was heated at 90° C. with stirring for 4 hours. The above reaction mixture was cooled to 25-30° C. The pH of the suspension was adjusted to 2.5 with 35% HCl (105 ml). The precipitate was collected by filtration and washed with water and dried in vacuo at 50° C. for 15 hours to give 3-amino-5-(4-fluorophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxylic acid as yellow powder. (29.6 g)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]([CH3:36])[CH3:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:37]([CH2:33][CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(=O)(=O)CC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and isobutylsulfonyl chloride to give 5,7-difluoro-2-(4-(isobutylsulfonyl)piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.05 (d, J=6.8 Hz, 6H), 2.11 (br s, 3H), 2.12-2.16 (m, 1H) 2.96 (d, J=6.8 Hz, 2H), 3.06 (br s, 4H), 3.33-3.37 (m, 8H), 3.69 (t, J=9.2 Hz, 4H), 6.53 (s, 1H), 7.16-7.20 (m, 1H), 7.29-7.32 (m, 1H), 7.52 (s, 1H), 7.79 (s, 1H,), 8.41 (s, 1H). Mass Spectrum (ESI) m/e=561.4 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]=1[NH2:12])C.C(O)(=O)C.[CH:18](N)=[NH:19]>C(OCCO)C>[Cl:11][C:9]1[CH:8]=[N:7][C:6]2[N:12]=[CH:18][N:19]=[C:4]([OH:3])[C:5]=2[CH:10]=1
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Reactant: N=CN
Solvent: CCOCCO
Solvent: CC(=O)O
Product: Oc1ncnc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 2-amino-5-chloro-nicotinic acid ethyl ester (1.5 g, 7.38 mMol) and formamidine acetate (3.1 g, 29.51 mMol) in 2-ethoxyethanol (50 mL) was heated at reflux overnight. The solution was cooled to room temperature, and allowed to stand for 2 hours. The resulting precipitate was collected by filtration, rinsed with a small amount of 2-ethoxyethanol followed by diethyl ether (10 mL), and allowed to air dry. The filtrate was concentrated in-vacuo, and the residue was triturated with methylene chloride. The resulting solids were combined with the solids from the earlier filtration, and this material was crystallized from methanol to yield 475 mg of tan needles as product, in three crops. MS (ES+)=182 (M+H)+. Yield=37%.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[C:4]([CH2:16][CH3:17])[CH:3]=1.[C-]#N.[Na+].[CH3:21][N:22](CCN(C)C)C>C1(C)C=C(C)C=C(C)C=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][C:5]=1[CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:21]#[N:22])[CH3:17]
Reactant: CCc1cc(Br)ccc1COC1CCCCO1
Reactant: CN(C)CCN(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: CCc1cc(C#N)ccc1COC1CCCCO1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of Intermediate 1 (2.9 g, 9.7 mmol), sodium cyanide (950 mg, 19.4 mmol), palladium (II) acetate (109 mg, 0.49 mmol), TMEDA (2.2 mL, 14.9 mmol), and 1,5-dis(diphenylphosphino)pentane (855 mg, 1.94 mmol) in mesitylene (50 mL) was bubbled with argon for 10 min. The degassed reaction mixture was heated to 170° C. for 16 h. After cooling to RT, the reaction mixture was diluted with water, stirred for another 10 min then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by MPLC (40% ethyl acetate in hexanes) gave rise to 2.23 g of Intermediate 4 as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[O:19])[CH:13]=[CH2:14].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH2:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([CH:20]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])[CH:13]=[CH2:14]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C=CCNC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: C=CCNC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
o-Nitrobenzaldehyde (7.6 g, 0.05 mole) and acetoacetic allylamide (7.1 g, 0.05 mole) are dissolved in benzene (40 ml) and thereto are added piperidine (0.2 ml) and acetic acid (0.6 ml), and the mixture is refluxed for 2 hours and the produced water is removed. After the stoichiometic amount of water is distilled off, the reaction is stopped. After the reaction, the reaction mixture is washed with 5% hydrochloric acid and then with water, and the solvent is distilled off under reduced pressure, and to the residue is added diethyl ether, and the obtained crude crystals are recrystallized from ethanol to give the title compound (9.6 g, yield 69.7%) as colorless needles, m.p. 128°-129° C.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([C@@H:23]2[CH2:29][NH:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>>[Br:16][C:17]1[CH:18]=[C:19]([C@@H:23]2[CH2:29][N:28]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][N:11]=4)[N:3]=3)[CH2:27][CH2:26][CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccc([C@@H]2CNCCCO2)c1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCO[C@H](c3cccc(Br)c3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (1.00 g, 4.49 mmol) and (R)-2-(3-bromophenyl)-[1,4]oxazepane (1.58 g, 5.39 mmol) was added triethylamine (1.36 g, 13.5 mmol) at room temperature. The mixture was stirred at room temperature for 9 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: ethyl acetate) to afford (R)-2-[2-(3-bromo-phenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A079) as white solid (1.65 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[NH:21][C:20](=[O:22])[CH:19]([CH3:23])[NH:18]1>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:18]1[CH:19]([CH3:23])[C:20](=[O:22])[NH:21][C:17]1([CH3:24])[CH3:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC1NC(C)(C)NC1=O
Product: CC1C(=O)NC(C)(C)N1C(=O)CNC(=O)OCc1ccccc1

Procedure:
The same procedure of the Example 2, starting from N-benzyloxycarbonylglycine and 2,2,5-trimethyl-4-imidazolidinone (m.p. 74°-75° C.; obtained from DL-alaninamide and acetone), afforded 1-(2-benzyloxycarbonylaminoacetyl)-2,2,5-trimethyl-4-imidazolidinone, m.p 170°-171° C., then the title compound m.p. 161°-163° C. dec. Mass spectrum (C.I., i--C4H10, 70 eV, 1.5 mA), m/z=186 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: Oc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 5-chloro-2-hydroxyaniline (25 mg, 0.173 mmol) similar to Example 185 and was isolated as a solid (7 mg, 16% yield). 1H NMR (CDCl3): 9.68 (d, J=0.9 Hz, 1H), 8.84 (t, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 7.89 (brs, 1H), 7.41 (s, 1H), 7.07 (m, 2H), 6.91 (d, J=8.7 Hz, 1H).
Reaction SMILES: [N+:1]([CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)([O-])=O>[Ni].C(O)C>[NH2:1][CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])CC12CCCN1CCC2
Agent: [Ni]
Solvent: CCO
Product: NCC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a suspension of Raney nickel (300 mg) in 5.0 ml of ethanol, 7a-nitromethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine (300 mg, 1.76 mmol, obtained in Example 1) was added and the resulting mixture was stirred for 1 hour at 20° C. under hydrogen atmosphere. The catalyst was filtered off, the filtrate was concentrated, and the resulting crude product was distilled in vacuo to afford 185 mg of the desired compound (Yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([CH:17]([OH:21])[CH:18]([CH3:19])[CH3:20])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: C=C(C)C(=O)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(O)C(C)C)c1

Procedure:
Dissolve N-methyl-5-(2-methylacryloyl)-N-propyl-isophthalamic acid methyl ester (80 mg, 0.26 mmol) in ethyl acetate (25 mL) under nitrogen. Add Raney® nickel (100 mg) and hydrogenate the reaction for 2 h at room temperature under an atmosphere of hydrogen gas (40 psi). Filter the reaction and concentrate to give the crude title product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(Br)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 6-bromopyridin-3-ol (0.500 g, 2.87 mmol) in DMF (3.0 mL) at 0° C. was added NaH (60% in mineral oil, 0.149 g, 3.74 mmol) portion-wise over a period of 10 min. The mixture was warmed to room temperature, stirred for 30 min, and methyl 3-(bromomethyl)benzoate (0.790 g, 3.45 mmol) was added in one portion. The reaction was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.726 g, 78% yield) as an off-white solid. LCMS, [M+H]+=322.0.
Reaction SMILES: N1(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCCC1>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1ccc(C(=O)On2nnc3ccccc32)cc1
Reactant: CCN1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCC(NC(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 84 %

Procedure:
To a mixture of 1.0424 g (4.1 mmole) of 4-amino-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.5257 g (4.1 mmole) of 4-amino-1-ethylpiperidine followed by 1.0372 g (10.3 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 65 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.8522 g 4-amino-N-(1-ethyl-piperidin-4-yl)-benzamide, as a white solid which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:6](O)=[O:7].[NH2:18]C(N)=O>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:6](=[O:7])[NH:18][C:15]2=[O:17]
Reactant: NC(N)=O
Reactant: O=C(O)c1cc(I)c(C(F)(F)F)cc1C(=O)O
Product: O=C1NC(=O)c2cc(C(F)(F)F)c(I)cc21

Procedure:
Prepared in analogy to Example A15(b) from 4-iodo-5-trifluoromethyl-phthalic acid and urea. Brown solid. MS (m/e): 339.9 ([M−H]−, 100%)
Reaction SMILES: C([Li])CCC.CCOCC.[C:11]1([C:17]#[C:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:17]([C:18]#[CH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC#Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C#CCc1ccccc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexane; 35 ml, 43.1 mmol) was added to dry ether (100 ml) under argon. The stirred solution was cooled to 5° C. and 1-phenyl-1-propyne (5.0 g, 43.1 mmol) was slowly added. On warming to room temperature the mixture turned bright red. After 18 hours, the mixture was cooled to 0° C., water was added, and the ether layer was separated. Concentration under reduced pressure gave an oil which was distilled to give benzyl acetylene as an oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(=O)(=O)(O)O.[C:15](O)(=O)[C:16](C)([CH3:18])[CH3:17].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.[Al].[N+]([O-])([O-])=O.[Ag+]>[C:16]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][N:4]=1)([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)C(=O)O
Reactant: O=C(O)c1cccnc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)cn1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
To a suspension of nicotinic acid (2.00 g, 16.2 mmol) in water (250 mL) was added concentrated sulfuric acid (1 mL, 18.8 mmol) and the mixture stirred under nitrogen to form a clear solution. Pivalic acid (1.83 g, 17.9 mmol) was added and stirring under nitrogen at ambient temperature continued for 10 minutes. Silver nitrate (125 mg, 0.74 mmol) was added followed by ammonium persulfate (295 mg, 1.3 mmol), the flask wrapped in aluminum foil to exclude light and the mixture heated to 90° C. under nitrogen. After 2 hours the reaction mixture was cooled to ambient temperature and the aqueous mixture concentrated in vacuo to a colorless solid. The solid was triturated with tetrahydrofuran and filtered. The solid residue was retriturated with methanol and filtered. Both filtrates were combined and concentrated in vacuo. The crude product was purified by reverse phase chromatography using a 85 g C-18 column gradient eluted from 10% acetonitrile in water to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo. The residue was lyophilized from water to give 6-tert-butylnicotinic acid as a colorless solid (139 mg, 4%).