Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:19])=[NH:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:29][C:30]([CH3:32])=[O:31]>>[C:30]([OH:2])(=[O:31])[CH3:32].[CH2:21]([NH:20][C:18]1[NH:17][C:15]([NH:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:16][C:30]([CH3:32])([CH3:29])[N:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CO
Reactant: CCCCCCCCNC(=N)NC(=N)NCCCCCCCC
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCCCCCCCC)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.6 ml of concentrated hydrochloric acid were added to 10.0 g (25.1 mmol) of N1,N5-dioctyl-biguanide dihydrochloride. The mixture was refluxed for 64 hours, and the solvent was distilled off under reduced pressure. To the residue were added 110 ml of ethanol, 60 ml of water and 10.1 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and then extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone to obtain 7.2 g of colorless crystals having a melting point of 91 to 93° C.
Reaction SMILES: O[CH:2]([CH2:10][CH3:11])[CH2:3][NH:4][C:5]([CH3:9])([CH3:8])[CH2:6]O.[NH3:12].[H][H]>>[CH3:9][C:5]1([CH3:8])[CH2:6][NH:12][CH:2]([CH2:10][CH3:11])[CH2:3][NH:4]1
Reactant: [H][H]
Reactant: N
Reactant: CCC(O)CNC(C)(C)CO
Product: CCC1CNC(C)(C)CN1
Yield: 70 %

Procedure:
In this example, another sample of 2,2-dimethyl-5-ethylpiperazine was prepared. Specifically, 150 cc of a Ni-Cu-Cr catalyst (1/8" diameter) was charged to a 0.815" ID tubular upward flow reactor. Two feeds, crude N-(2'-hydroxybutyl)-2-amino-2-methyl-1-propanol and ammonia were pumped through the catalyst bed at a rate of 0.30 lb/hr and 0.70 lb/hr, respectively. Hydrogen was also passed through the reactor at a rate of about 13 liters/hr. At 215° C. and 2200 psig, the products were collected. The resulting reaction mixture was vacuum distilled and then fractionally distilled at atmospheric pressure (b.p. 192° C.). About 70% yield of 2,2-dimethyl-5-ethylpiperazine was obtained.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(C)C)(C)C.COC1C=CC(O)=CC=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[Br-:28].[C:1]([O:6][CH2:7][CH2:8][N+:9]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCCCCCCCCBr
Reactant: C=C(C)C(=O)OCCN(C)C
Agent: COc1ccc(O)cc1
Solvent: CC(C)OC(C)C
Product: C=C(C)C(=O)OCC[N+](C)(C)CCCCCCCCCCCC
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a two-necked flask provided with a reflux condenser and a dropping funnel were introduced 94.3 g (0.6 mol) of methacryloyloxyethyl-N,N-dimethylamine, 78 g of isopropyl ether and 0.1 g of hydroquinone monomethyl ether, which was employed as a polymerization inhibitor, and mixed homogeneously. After dropping 149.5 g (0.6 mol) of 1-bromododecane thereinto within about 15 minutes, the mixture was allowed to stand overnight under stirring at room temperature. Then the reaction mixture was washed with 500 ml of isopropyl ether to obtain crystals of methacryloyloxyethyl-N,N-dimethyldodecylammonium bromide.
Reaction SMILES: CSC.C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=1)C1C=CC=CC=1.O>C(Cl)Cl>[CH3:26][S:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[OH:11])=[CH:20][CH:21]=1
Reactant: CSc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: CSc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.6 %

Procedure:
In a nitrogen stream, dimethylsulfide (7.25 mL, 138 mmol) and a boron trifluoride-diethyl ether complex (2.1 mL, 8.8 mmol) were added to a solution of 1-benzyloxy-(4-methylsulfanylbenzyl)benzene (1.9 g, 5.9 mmol) in methylene chloride (15 mL) under cooling with ice, and the reaction mixture was stirred for 48 hours while gradually raising its temperature to room temperature. Water was added thereto under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.19 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=1Cl)[NH:6]2.[NH2:31][CH2:32][C@@H:33]([OH:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43].CCN(CC)CC>CCO>[Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=1[NH:31][CH2:32][CH:33]([OH:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43])[NH:6]2
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Reactant: CN1CCC(N2C(=O)c3cc4[nH]c(-c5c(Cl)cc[nH]c5=O)nc4c(Cl)c3C2=O)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1

Procedure:
A solution of 4-chloro-2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (18 mg, 0.04 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (12.0 mg, 0.06 mmol) and Et3N (0.2 mL, 1.43 mmol) in EtOH (2.0 mL) was heated at 100° C. for 19 h and then concentrated to result a residue which was subjected to HPLC purification to furnish the title compound in TFA salt form (3.98 mg, 14%). 1H NMR (DMSO-d6) δ 1.95 (m, 2H), 2.15 (s, 3H), 2.19 (s, 3H), 2.51 (m, 2H), 2.80 (s, 3H), 3.18 (m, 2H), 3.50-3.80 (4H), 4.02 (m, 2H), 4.15 (m, 1H), 4.30 (m, 1H), 5.50 (br s, 1H, NH), 6.25 (d, J=8 Hz, 1H), 6.80-6.94 (3H), 7.40 (m, 1H), 8.08 (s, 1H), 9.49 (br s, 1H), 10.90 (br s, 1H), 11.36 (d, J=6 Hz, 1H); ESI-MS m/z 605.3 (MH+).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:10].[NH2:20][CH2:21][C:22]1[NH:23][C:24](=[O:32])[C:25]2[CH:31]=[CH:30][CH:29]=[N:28][C:26]=2[N:27]=1>CN(C1C=CN=CC=1)C.ClCCl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C:9](=[O:10])[NH:20][CH2:21][C:22]1[NH:23][C:24](=[O:32])[C:25]2[CH:31]=[CH:30][CH:29]=[N:28][C:26]=2[N:27]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2ncccc2c(=O)[nH]1)OCc1ccccc1Cl
Reaction time: 8 h

Procedure:
Triethylamine (0.26 ml), 2-chlorobenzyl chloroformate ([39545-31-8], 130 mg) and DMAP (8 mg) were added to a solution of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (25.1, 150 mg) in dichloromethane (3 ml). The mixture was kept overnight at r.t., and then diluted with dichloromethane and washed with water. After drying (Na2SO4) and evaporation of the solvent, the title compound was isolated from the reaction mixture by preparative, reversed-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min). MS: m/e=343.0 [M−H−].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][C@@H:48]([N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]2[CH:66]=[CH:65][C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH:58]=2)[C:49](=[O:52])[NH:50][CH3:51])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([C@@H:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:44]1[CH:43]=[CH:42][C:41]([F:40])=[CH:46][CH:45]=1)[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.22 g; 0.89 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.20 g; 1.02 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.53 g of (2-((((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylcarbamoylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)-methoxy)-1,1-dimethylethyl)carbamic acid tert-butylester.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21]([C:24]([O:26]CC)=[O:25])[CH:20]=[N:19][C:18]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=[N:19][C:18]=23)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Yield: 99.3 %

Procedure:
A mixture of 3-(4-benzylphenyl)-6-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine 1.35 g), sodium hydroxide (1.50 g), ethanol (35 ml) and water (35 ml) was stirred under heating reflux for 2 hours. Then, to the reaction mixture was added water (50 ml), and hydrochloric acid was added at 0° C. to adjust to acid. After stirring for 30 minutes, the precipitate was separated by filtration, washed with water, and dried to give the title compound (1.24 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Br)cc(C=O)cc21
Reactant: OB(O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ncc2c(-c3ccncc3)cc(C=O)cc21
Temperature: 120 °C
Yield: 62.6 %

Procedure:
To a solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (50 mg, 0.14 mmol) and pyridine boronic acid (20 mg, 0.16 mmol) in 10:1 DMF/water (1 mL) was added K2CO3 (36 mg, 0.26 mmol) and tetrakistriphenylphosphine palladium (7.5 mg, 0.007 mmol). The mixture was heated to 120° C. under microwave irradiation for 20 min. Ethyl acetate (20 mL) was added and the solution was washed with water (2×5 mL) and brine (5 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (3:1 EtOAc/Hex) to give the title compound as a pale yellow solid (31 mg, 62%). MS ESI [M+H]+, calcd for [C19H23N3O2Si+H]+ 354.2; found m/z 354.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH:12]2[C:17](=O)[CH2:16][CH2:15][O:14][CH2:13]2)[NH:8][N:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:7]1[N:8]2[C:9]([O:11][C:12]3[CH2:13][O:14][CH2:15][CH2:16][C:17]=32)=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2oc3c(n2n1)CCOC3
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A mixture of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate (254 mg, 1 mmol) and methane sulfonic acid (192 mg) in 7 ml of acetic acid and toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate aqueous bicarbonate solution. The organic layer was washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue was purified by silica gel chromatography eluting with ethyl acetate/hexane to give 120 mg (51%) of the desired product as white solid. Mp; 116-118° C.; Electrospray-MS m/z 237.0 (M+H)+
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].CN(C=O)C>O1CCOCC1>[CH3:34][C:27]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:10](=[O:11])[NH:12][CH:21]([C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1cccc([N+](=O)[O-])c1

Procedure:
30.6 mg (0.15 mmol) N-[3-(trifluoromethyl)phenyl]urea are shaken together with 45.3 mg (0.3 mmol) 3-nitrobenzaldehyde, 39 mg (0.3 mmol) ethyl 3-oxobutanoate and 90 mg polyphosphoric acid ethyl ester [freshly prepared according to the procedure of Cava et al., J. Org. Chem. 34, 2665 (1969)] in 0.5 ml dioxan and 0.1 ml DMF at 80° C. for 18 hours. After adding 200 μl DMF, the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; flow rate 25 ml/min; wavelength: 220 nm; injection volume: approx. 800 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.CC#N.O>C(O)=O>[F:17][CH:2]([F:1])[CH2:3][N:4]([CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=2)[CH2:26][CH2:27]1
Reactant: O=c1[nH]c(CNCC(F)F)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC(F)F)CC1

Procedure:
Following general procedure of Example 5, the title compound was prepared (0.046 g) from 2-((2,2-difluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (0.18 g, 0.73 mmol, 1 eq.) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (0.20 g, 0.73 mmol, 1 eq.). 1H NMR (400 MHz, MeOD) δ ppm 8.00-8.18 (m, 2H), 7.17-7.36 (m, 2H), 5.83-6.44 (m, 1H), 4.56-4.68 (m, 2H), 4.42-4.52 (m, 2H), 4.30-4.42 (m, 2H), 3.80-4.08 (m, 4H), 3.66-3.79 (m, 3H), 3.42-3.61 (m, 1H), 3.09-3.26 (m, 1H), 2.56-2.71 (m, 2H), 1.93-2.28 (m, 4H). HRMS calculated for C24H28F3N4O4 493.2063. found (ESI, [M+H]+) 493.2062. MS (ESI) m/z 493.2 (M+H)+. Retention time: 4.65 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][NH:10]3)=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][N:10]3[C:26](=[O:27])[CH2:25][N:22]2[C:23]([CH3:24])=[C:19]([Cl:18])[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CN2CC3CC2CN3)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CC3CC2CN3C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-Chloro-3-methoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane (96 mg), (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)acetic acid (96.8 mg), triethylamine (0.252 mL) in DMF (2 mL) was stirring at room temperature and a solution of T3P (50% in EtOAc, 0.55 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 h and purified on preparative HPLC to afford 1-[5-(4-Chloro-3-methoxybenzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)ethanone as white powder. LCMS (ES) M+H 477.0, Rf 3.975 min (acetonitrile/H2O 20-95% method).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[ClH:9].[H][H]>CO.[Pt]>[ClH:9].[NH2:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)/C=C(/C)N
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)CC(C)N
Yield: 96 %

Procedure:
5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of a 9.3% strength solution of 17 g (43 mmol) of HCl gas in anhydrous methanol and 0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave. The hydrogenation was carried out for 3 hours at 21-25° C. under 5-10 bar of hydrogen. The catalyst was then filtered off and the solvent was completely removed by distillation on a rotary evaporator. 6.34 g of pure methyl (RS)-3-amino-butyrate hydrochloride were obtained as an 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].[C:12]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1C=CC=CC=1>[NH:1]1[CH2:4][CH2:5][CH2:8][CH2:9][CH2:10]1.[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OCCOc1ccccc1
Solvent: c1ccccc1
Product: C1CCNCC1
Product: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCCOc1ccccc1

Procedure:
Starting from a mixture of 2-nitrobenzaldehyde (3.02 g), 2-phenoxyethyl acetoacetate (4.44 g), piperidine (272.5 mg) in benzene (10.8 ml) was obtained an oil (8.0 g) of 2-phenoxyethyl 2-(2-nitrobenzylidene)acetoacetate. Thus obtained oil was treated with ethyl 3-amino-4,4-diethoxycrotonate (4.34 g) to give an oil of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Cl.O>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1nn[nH]c1N
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Reaction time: 1 h

Procedure:
A stirred, ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (635 mg, 5.00 mmole) in dry dimethylformamide (20ml) is treated in one portion with sodium hydride (240 mg of a 5% dispersion in mineral oil, 120 mg NaH, 5.0 mmol). After 15 min 3,4-dichlorobenzyl chloride (0.977 g, 5.00 mmol) is added. The mixture is stirred 1 hour, poured into water (20 ml), acidified to pH 6 with glacial acetic acid, and filtered. The solid is washed with water, dried, and chromatographed to provide 5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NCC(=O)c1ccc(OC(=O)c2ccccc2)c(O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen was reacted with 16 g. of sodium methoxide and then with 14 g. of benzoyl chloride. The product was isolated as the free base, 3-hydroxy-4-(benzoyloxy)phenyl tert-butylaminomethyl ketone [20 g.; m.p. 150-165° C. (dec.) (uncorr.)], which was converted to 13 g. of its methanesulfonate, m.p. 245° C. (dec.)(uncorr.). By catalytically hydrogenating this salt, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][O:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O.[Li+].[OH-].O.O1CCOCC1>>[C:1]1([C:7]2[C:8]([NH:12][CH:14]([C:13]([OH:18])=[O:17])[CH3:16])=[N:9][O:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nonc1-c1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(Nc1nonc1-c1ccccc1)C(=O)O

Procedure:
Following General Procedure II-D and using 4-phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich), the ethyl ester was prepared. Following General Procedure II-A, Method B (LiOH/H2O/dioxane) and using the ethyl ester, the title compound was prepared.