Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:63][CH:64]5[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]5)=[O:26])=[CH:23][CH:22]=4)=[N:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc2N(C)C1=O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc2N(C)C1=O
Reaction time: 0.08 h
Yield: 61 %

Procedure:
A mixture of 0.02 g (0.00005 mole) of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-benzoic acid (I-5), 0.023 g (0.00006 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.018 mL (0.0001 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.0085 g (0.000075 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.015 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-6) as a white solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CS(=O)(=O)c1ccc(-c2cc(F)cc(F)c2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3,5-difluoro-benzeneboronic acid. Light brown solid. MS (m/e): 311.1 ([M−H], 100%).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1([CH3:13])[C:9]([O:11][CH3:12])=[O:10].CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][CH:3]([OH:2])[C:4]([CH3:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:5]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)C1(C)CNCCC1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C1(C)CN(c2ncc(Br)cn2)CCC1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-piperidine-3-carboxylate hydrochloride (0.4 g, 1.91 mmol) in EtOH (10 mL) was added DIPEA (1.7 mL, 9.55 mmol) at rt. The resulted mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.37 g, 1.91 mmol). The reaction mixture was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue was purified over 100-200 M silica-gel by using 25% EtOAc: hexane to obtain the product as an off white solid (0.345 g, 55%). MS: 330.12 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25]>O1CCCC1>[N:1]([C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1)=[C:24]=[O:25]
Reactant: CC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2cccc(N=C=O)c2)C1=O
Temperature: 25 °C

Procedure:
Seventy-three g. of N-m-aminophenyl-2,2-dimethylsuccinimide, as prepared in Example II, was dissolved in 800 ml. of tetrahydrofuran containing 75 g. of triethylamine, cooled in an ice bath, and added to 60 g. of phosgene in 400 ml. of tetrahydrofuran maintained at about 0° C. in a drying and isopropanol bath. The mixture was allowed to warm to room temperature and the triethylamine hydrochloride was filtered off and the tetrahydrofuran removed under vacuum on the rotary evaporator. Yield was 84 g. of material product having a nD30 of 1.5470. The product was identified as the title compound by analysis of infrared spectra and was used without further purification.
Reaction SMILES: [C:1]([N:5]1[CH2:10][C:9]2[CH:11]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:13]=[C:14]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:8]=2[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([Mg][Cl:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(OCC)C.C(O)C>C1COCC1.Cl>[ClH:36].[C:25]([C:12]1[CH:13]=[C:14]([C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:8]([OH:7])=[C:9]([CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:11]=1)([CH3:27])([CH3:26])[CH3:28]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C)(C)c1cc2c(c(-c3ccc(C(F)(F)F)nc3)c1)OCN(C(C)(C)C)C2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN(CC2CCCCC2)C(C)(C)C)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 3,6-di-tert-butyl-8-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (Example 75) (250 mg, 0.63 mmol) in THF (10 mL) under argon was added dropwise a 2.0 M solution of cyclohexylmagnesium chloride in diethyl ether (0.41 mL, 0.82 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered, and the crude product purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes. The product was dissolved in a 1.25 M solution of hydrochloric acid in ethanol (5 mL, 6.3 mmol), the mixture stirred for 30 minutes then concentrated under reduced pressure and the product triturated with hexane to give 4-(tert-butyl)-2-((tert-butyl(cyclohexylmethyl)amino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (162 mg, 50% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC(C)([O-])C.[K+]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:2]2[N:3]=[C:4]([N:8]3[C:16]4[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=4)[CH2:10][CH2:9]3)[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1ncnc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(N3CCc4cc(S(C)(=O)=O)ccc43)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11a was dissolved in THF. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 1 eq) and potassium tert-butoxide (22 mg, 1 eq) were added and the mixture was stirred at room temperature for 3 h, then was quenched with water. The mixture was extracted with ethyl acetate twice, and the organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated and the residue taken up in methanol and dichloromethane and purified by preparative HPLC to give 11-1, LCMS 476.2 (MH+), tR=3.68 (Method 6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:20])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)Cc1ccccn1
Reactant: Brc1ccc2c(c1)CCN2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccn1)N1CCc2cc(Br)ccc21
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a solution of 5-bromoindoline (5.0 g), 2-pyridinylacetic acid hydrochloride (4.82 g) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (15.8 g) in N,N-dimethylformamide (100 mL) was added dropwise diisoprpylethylamine (6.53 g) at ambient temperature and the mixture was stirred at the same temperature for 20 hours. The mixture was poured into a mixture of ethyl acetate and water and the separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 5-bromo-1-(2-pyridinylacetyl)indoline (5.23 g) as a light-brown powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[C:23](=[O:24])[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:15]2[C:29]=1[CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1)=O)C>O1CCCC1>[OH:9][CH2:10][C:12]1[N:13]=[C:14]2[C:23](=[O:24])[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[N:15]2[C:29]=1[CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2c(Cc3ncc[nH]3)c(CO)nc12
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a suspension of lithium aluminium hydride (400 mg, 10.5 mmol) in dry tetrahydrofuran (200 ml) was added 2-ethoxycarbonyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (3.6 g, 8.8 mmol) in small portions. After 20 min. at 25° C. the temperature was raised to reflux for 2 h. The reaction mixture was cooled to room temperature, quenched with water and then filtered, The solvent was evaporated in vacuo and the residue dissolved in 20% sulphuric acid. The precipitate was filtered off and the liquid phase added potassium hydroxide to pH 11. The product was isolated by continuous liquid/liquid extraction (ethyl acetate) overnight to give 2.1 g (67%) of the title compound. M.p. 215° C.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[La+3:15].[Cl-].[Cl-].[Cl-].[Eu+3].[Cl-].[Cl-]>>[C:3]([O-:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[La+3:15].[C:3]([O-:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:3]([O-:13])(=[O:12])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: [Cl-]
Agent: [Eu+3]
Agent: [La+3]
Product: O=C([O-])C=Cc1ccccc1

Procedure:
Europium cinnamate, [(C6H5CH=CHCOO)3Eu], was obtained by following the procedure of Comparative Example 4, except that the quantity of sodium hydroxide was changed from 1.698 g to 1.132 g, the quantity of cinnamic acid was changed from 6.289 g to 4.193 g and 5.0 g of lanthanum chloride was substituted by 3.456 g of europium chloride (EuCl3.6H2O; purity 99.9%). Then, the total quantity of lanthanum cinnamate obtained as described in Comparative Example 4 and the total quantity of europium cinnamate described above were placed in an agate mortar and thoroughly mixed until a homogeneous mixture was obtained. Consequently, there was obtained a physical mixture of 0.6 lanthanum cinnamate and 0.4 europium cinnamate;
Reaction SMILES: [CH3:1][O:2][CH:3]([O:5][CH3:6])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1>CCOCC>[CH3:4][CH:3]1[O:5][CH2:6][CH2:17][CH:7]2[CH:1]([CH2:9][CH2:8][CH2:7][CH2:12][CH2:11][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[O:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(C)OC
Solvent: CCOCC
Product: CC1OCCC2CCCCCCCCCCC2O1
Temperature: 70 °C

Procedure:
A mixture of 240 gm (1 mol) of the diol prepared according to (c) above, 90 gm (1 mol) of acetaldehyde dimethyl acetal, and 0.2 gm of p-toluene sulfonic acid was refluxed for five hours at 70° C. After the reaction was completed, the reaction mixture was taken up in ether, washed neutral with 2 N sodium hydroxide solution, washed with water, and then dried over anhydrous sodium sulfate. The ether and methanol were distilled off, and then the residue was distilled in the oil-pump vacuum. The 14-methyl-13,15-dioxabicyclo[10.5.0]heptadecane obtained was a colorless liquid with the following characteristics:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCc1ccccc1
Reactant: CCCCCCCN=C=S
Solvent: c1ccccc1
Product: CCCCCCCNC(=S)NCc1ccccc1
Yield: 105.9 %

Procedure:
To a solution of 3.1 grams (0.02 mole) of n-heptyl isothiocyanate dissolved in 25 milliliters of benzene, was added 2.1 grams (0.02 mole) benzylamine. The resulting exothermic reaction resulted in a temperature rise from 24° C. to 35° C. The mixture was then refluxed for 20 minutes on the steam-bath until the mixture reached neutral pH and the mixture was evaporated under vacuum to yield 5.6 grams of n-heptyl-3-benzyl thiourea, ND30 =1.5513.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: COC(=O)C=Cc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Yield: 82.3 %

Procedure:
To a suspension of the sulfonamide of Example 331 (c) (2.1 g, 4.54 mmol) in ethanol (125 mL) under nitrogen was added 10% Pd/C (0.6 g). The mixture was placed on a Parr hydrogenator at 50 psi of hydrogen for 2 hours, the catalyst was removed by filtration and the solvent was removed in vacuo. The residue was recrystallized from Et2O/MeOH, extracted with CH2Cl2, washed with water, then brine and was dried over MgSO4. The solvent was removed in vacuo to afford 1.41 g (82%) of N-methyl-N-(4-methoxybenzyl)-4-(2-(methoxycarbonyl)ethyl)phenylsulfonamide as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl.[CH3:21]O>>[C:1]1([CH:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH3:21])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C(SCc1ccncc1)c1ccccc1
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(SCc1ccncc1)c1ccccc1
Reaction time: 16 h

Procedure:
Sodium 2-phenyl-2-(4-picolylthio)acetate was dissolved in methanol and dry hydrogen chloride added slowly so as to maintain gentle reflux for 1 hour. After cooling and stirring for approximately 16 hours, the reaction mixture was filtered and concentrated to yield title product (11.6 g.; oil; ms, calcd.: m/e 273; found: 273, 214, 150, 136, 124, 121, 105, 77, 65).
Reaction SMILES: C([O-])(O)=O.[Na+:5].[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[C:15]([OH:26])[C:16]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[N:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=1>CC(C)=O>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[C:15]([OH:26])[C:16]([C:19]([NH:21][CH2:22][C:23]([O-:25])=[O:24])=[O:20])=[N:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=1.[Na+:5]
Reactant: O=C(O)CNC(=O)c1ncc(-c2cccc(F)c2)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C([O-])CNC(=O)c1ncc(-c2cccc(F)c2)cc1O

Procedure:
To a vial containing NaHCO3 (41.09 mg) is added a solution of {[5-(3-fluoro-phenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetic acid (6) in acetone (0.64 mL of a 400 mg sample in 5.12 mL). The solution is stirred and the desired product isolated by concentration in vacuo.
Reaction SMILES: O.[O:2]=[C:3]([CH2:5][N:6]([C:8](=[NH:10])[NH2:9])[CH3:7])O.[ClH:11]>>[CH3:7][N:6]1[C:8]([NH2:10])=[N:9][C:3](=[O:2])[CH2:5]1.[ClH:11]
Reactant: CN(CC(=O)O)C(=N)N
Agent: Cl
Solvent: O
Product: CN1CC(=O)N=C1N

Procedure:
Shortening the reaction time from 20 hours to 10-12 hours resulted in a decrease in the conversion of creatine monohydrate to CEE HCl to about 76 to 83%. Increasing the reaction time to greater than 20 hours resulted in no significant increase in the conversion of creatine monohydrate to CEE HCl. Such longer reaction times, however, did result in the increased formation of the undesirable product creatinine HCl.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([C@H:30]3[CH2:35][CH2:34][C@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]\[C:46]([OH:48])=[O:47]>C(OC(=O)C)C>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]\[C:46]([OH:48])=[O:47].[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]\[C:46]([OH:48])=[O:47].[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]\[C:46]([OH:48])=[O:47].[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]([O:28][CH3:29])[CH:12]=3)=[CH:9][N:8]([C@H:30]3[CH2:31][CH2:32][C@@H:33]([N:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)[CH2:34][CH2:35]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(-c2cn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1

Procedure:
Trans-benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)carbamate was dissolved in ethylacetate and treated with maleic acid (280 mg) in ethylacetate. The resulting solid was filtered under a stream of nitrogen and dried in vacuo for 4 hr to give Cis-benzyl N-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)carbamate tri-maleate salt (580 mg) as a cream solid. M.pt. 158° C. (dec.)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH3:19])=O.[CH:20]1([NH:23][C:24]2[S:25][CH2:26][C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:20]1([NH:23][C:24]2[S:25]/[C:26](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH2:16][CH2:17][O:18][CH3:19])/[C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1
Reactant: COCCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(NC2CC2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCOc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile (example 77b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 395 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[C:14]=1[F:21])[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:25].[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[C:17]([N+:26]([O-:28])=[O:27])[C:16]([F:19])=[C:15]([F:20])[C:14]=1[F:21])[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:25]
Reactant: O=C(O)c1cn(-c2ccc(F)c(F)c2F)c2cc(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2cc(F)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 72 h
Yield: 74.9 %

Procedure:
To 10 ml of conc. sulfuric acid was added 830 mg of 6,7-difluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluorophenyl)-quinoline-3-carboxylic acid. Potassium nitrate (710 mg) was added in portions to the solution, which was stirred at 100° C. for 3 days. The reaction solution was allowed to cool, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration, washed with water, ethanol and diethyl ether to give 700 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[N:48]1([CH2:53][CH2:54][CH2:55][CH2:56][C:57](Cl)=[O:58])[CH:52]=[N:51][N:50]=[N:49]1>C(Cl)Cl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:57](=[O:58])[CH2:56][CH2:55][CH2:54][CH2:53][N:48]2[CH:52]=[N:51][N:50]=[N:49]2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: O=C(Cl)CCCCn1cnnn1
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CCCCn1cnnn1
Reaction time: 0.5 h

Procedure:
1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are dissolved in 30 ml of methylene chloride, and, at 0°, 0.41 ml of pyridine, 50 mg of 4-dimethylaminopyridine and then, dropwise, a solution of 0.87 g of 5-(tetrazol-1-yl)-valeric acid chloride in 15 ml of methylene chloride are added. After stirring for 30 minutes at 0°, the solid material is filtered off over Hyflo and the filtrate is washed with aqueous sodium bicarbonate solution and then with brine. After drying over MgSO4, the solution is concentrated by evaporation. The residue is purified by chromatography over silica gel (eluant toluene/ethyl acetate: 9:1 to 1:1). TLC (ethyl acetate) Rf =0.33; IR (CH2Cl2): 1750, 1690, 1620 cm-1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:12]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
A suspension of 3.65 g (0.022 mol) of 2-chloroquinoline, 6.88 g (0.08 mol) of piperazine and 1.12 g (0.02 mol) of potassium carbonate in 150 ml of toluene is refluxed for five hours. After cooling it is extracted twice with water, the organic phase is dried over sodium sulphate and the solvent is concentrated by evaporation. The residue is combined with methanol. Then it is filtered and the filtrate is concentrated by evaporation.