Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Br:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Br.C(O)(=O)C>C(OCC)C>[BrH:28].[CH2:25]([C:22]1[CH:21]=[N:20][C:19]([N:18]([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:24][CH:23]=1)[CH3:26]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: BrCCCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cnc(N(CCCc2ccccc2)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and (3-bromopropyl)benzene as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)Cl.[S-:22][C:23]#[N:24].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH2:11][S:22][C:23]#[N:24]
Reactant: COc1cc(Cl)c(Cl)cc1Cl
Reactant: N#C[S-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: ClP(Cl)Cl
Product: N#CSCOc1cc(Cl)c(Cl)cc1Cl
Temperature: 160 °C
Yield: 65.1 %

Procedure:
In a 50 ml. flask equipped with a thermometer, magnetic stirrer, oil bath, and fractionating distillation head place 20.0 g. (0.095 mole) 2,4,5-trichloroanisole and 19.7 g. (0.095 mole) phosphorous pentachloride. The mixture is stirred and heated at 160° C. for 3 hours. As reaction takes place, phosphorous trichloride distills out of the flask. The mixture is heated at 180° C. for 0.5 hour, cooled, and the intermediate product α,2,4,5-tetrachloroanisole is distilled; b. p. 123° C. at 1.5 mm Hg., yield 18.6 g. (81%). This product is dissolved in 120 ml. acetone and 8.1 g. (0.083 mole) dried potassium thiocyanate is added in one portion. The mixture is stirred at ambient temperature for 48 hours, poured into 900 ml. ice water, and extracted with ether. The ether extracts are washed with cold 0.5 N sodium hydroxide and water, dried (MgSO4), and concentrated. The crude product is recrystallized from hexane to give compound (I) 14.5g (71%), as colorless needles, m.p. 103°-105° C. Calcd. for C8H4Cl3NOS: C, 35.78; H, 1.50; Cl, 39.61; N, 5.22; S, 11.94. Found: C, 35.71; H, 1.68; Cl, 39.2; N, 5.14; S, 11.99.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2.[N-:14]=[N+:15]=[N-:16].[Na+].[CH:18](OCC)(OCC)OCC>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]3)[CH:18]=[N:16][N:15]=[N:14]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1)CCC2C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2cc(-n3cnnn3)ccc21
Temperature: 25 °C

Procedure:
A solution of 5-aminoindane-1-carboxylic acid (2.95 g, 16.7 mmol), sodium azide (1.20 g, 18.3 mmol) and triethyl orthoformate (7.42 g, 50.1 mmol) in 20 mL of actic acid was heated to 100° C. for 3 hrs. After the reaction was completed, the mixture was cooled to ambient temperature. The solution was removed under vacuum and the residue was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified with silica gel column chromatograph to give the crude product, then re-crystalization from DCM to yield 5-(1H-tetrazol-1-yl)indane-1-carboxylic acid. 1H-NMR (400 MHz, DMSO) δ ppm 10.0 (s, 1H), 7.75 (s, 1H), 7.66˜7.69 (m, 1H), 7.55 (d, J=8.1 Hz, 1H), 4.02˜4.06 (m, 1H), 2.88˜3.08 (m, 2H), 2.31 (q, J=8.1 Hz, 2H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:28]([O:30]C)=O)=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]21.O1[CH2:36][CH2:35][CH2:34]C1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:28]([CH:34]2[CH2:35][CH2:36]2)([CH:1]2[CH2:3][CH2:2]2)[OH:30])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 4.8 mL, 4.8 mmol) was added to a stirred solution of methyl 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (400 mg, 0.974 mmol) in tetrahydrofuran (5.0 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (320 mg, 0.691 mmol, 71%).
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32](=[O:35])[CH2:33]Br)=[CH:31][C:26]=2[O:25][CH2:24]1>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:33]=1[C:32]([C:30]1[CH:29]=[CH:28][C:27]2[O:23][CH2:24][O:25][C:26]=2[CH:31]=1)=[O:35]
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Reactant: N#CN
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Product: Nc1nc(Nc2ccc(N3CCN(CC4CC4)CC3)cc2)sc1C(=O)c1ccc2c(c1)OCO2

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-[(benzo[1,3]dioxol-5-yl)ethanone (of Example 11) following the procedure used in Example 24 Mass spectrum (ES) MH+=478.
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[N:4]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:20][CH:21]([C:3]1[O:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[N:4]=1)[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cn1cc(-c2noc(C(Cl)(Cl)Cl)n2)c2ccccc21
Reactant: NCCN1CCCCC1
Product: Cn1cc(-c2noc(C(N)CN3CCCCC3)n2)c2ccccc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
5-Trichloromethyl-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole (0.100 g, 0.316 mmol) (D8) was dissolved with stirring in 1-(2-aminoethyl) piperidine (0.8 ml) and heated to 120° C. After 0.5 h, the reaction mixture was allowed to cool and was partitioned between EtOAc and water. The organic layer was then washed with water (1×), dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil which was purified by silica gel chromatography (10% MeOH in EtOAc as eluant) to give the title compound as a colourless oil that crystallised on standing (0.095 g, 93%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][CH2:8][CH:9]=O.C([O-])(O)=O.[Na+]>CO.CC(O)=O.Cl>[Cl:7][CH2:8][CH2:9][N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: O=CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O[C@@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of (R)-3-hydroxypyrrolidine (0.47 g, 5.5 mmol) in MeOH (14.4 mL) and AcOH (1.44 mL) was added chloroacetaldehyde (0.86 mL, 5.5 mmol, 50% in H2O solution) and picolineborane complex (0.58 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h. Then additional picoline borane complex (0.29 g, 2.7 mmol) was added. The reaction mixture was stirred for an additional 0.5 h. Then the reaction mixture was diluted with HCl (30 mL, 10% in H2O) and stirred for 0.5 h at ambient temperature. The mixture was slowly basified with solid NaHCO3 (7.85 g) and extracted with EtOAc (3×20 mL). The organics extracts were dried (Na2SO4) and concentrated to yield the title compound (0.19 g, 23%) as a light yellow oil. 1H NMR (300 MHz, CD3OD) δ 4.36-4.32 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 2.91-2.76 (m, 4H), 2.66-2.52 (m, 3H), 2.16-2.09 (m, 1H), 1.74-1.70 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1cccc(N)c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(N)c1C
Temperature: 12 °C

Procedure:
363 g of 2,3-xylidine are run into 1.8 of pure sulphuric acid while the temperature is kept at 40° C. To this solution, cooled to 12° C., a sulphonitric mixture (132 ml of nitric acid (d=1.52) and 180 ml of pure sulphuric acid) is added dropwise over 1 hour, the temperature not exceeding 15° C. After 15 minutes the mixture is poured onto 6 kg of ice with stirring.
Reaction SMILES: O.O.[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[C:12]1(=[CH:15][C:16](OC)=[O:17])[CH2:14][CH2:13]1.Cl.FC(F)(F)C(O)=O>O.CN(C)C=O>[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]2[C:5]=1[C:16](=[O:17])[CH2:15][C:12]1([O:11]2)[CH2:14][CH2:13]1
Reactant: COC(=O)C=C1CC1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CC2(CC2)Oc2cc(O)cc(O)c21
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Under argon, 112 g (690 mmol) of 1,3,5-trihydroxybenzene dihydrate are dissolved in 230 ml abs. dimethylformamide, 28.82 g (230 mmol) of methyl cyclopropylideneacetate (Example 41A) and 20 g of 4 Å molecular sieve (as powder) are added and the mixture is stirred at a bath temperature of 130° C. overnight. 1 liter of 1 N hydrochloric acid is then added, and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 230 ml (2.99 mol) of trifluoroacetic acid are added to the product obtained, and the mixture is heated to 75° C. and stirred for 8 hours. The mixture is then cooled, water is added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified on silica gel (mobile phase: dichloromethane/methanol 100:1→100:3). The product fractions are combined and concentrated. Dichloromethane is added to the residue obtained, the mixture is stirred briefly and the precipitate is filtered off with suction and dried under high vacuum. This gives 2.25 g (5% of theory) of the target compound. The mother liquor is then purified again on a silica gel column (mobile phase: dichloromethane/methanol 100:1). This gives a further 3.41 g (7% of theory) of the title compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>>[C:1]1([S:7]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH:15]=[CH:16]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc2[nH]ccc2c1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Yield: 73 %

Procedure:
The title compound was prepared from benzene sulfonyl chloride and 5-fluoro-1H-indole, according to Method A, described above. Yield 73%; 1H NMR (CDCl3) δ 7.77-7.82 (dd, J=9 Hz, 1H), 7.71-7.74 (m, 2H), 7.47 (d, J=4 Hz, 1H), 7.30-7.45 (m, 3H), 7.03-7.07 (dd, J=9 Hz, 1H), 6.87-6.95 (dt, J=9 Hz, 1H), 6.51 (d, J=4 Hz, 1H); MS (AP+) m/z 276.0 (M++1), 214.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[Cl:11][C:12]1[N:17]=[C:16]2[C:18]([CH:21]=O)=[CH:19][S:20][C:15]2=[CH:14][CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]2[C:18]([CH2:21][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])=[CH:19][S:20][C:15]2=[CH:14][CH:13]=1
Reactant: CCOC(OCC)[C@H](C)N
Reactant: O=Cc1csc2ccc(Cl)nc12
Product: CCOC(OCC)[C@H](C)NCc1csc2ccc(Cl)nc12
Yield: 30.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 1.98 g (13.4 mmol) was reacted with 5-chlorothieno[3,2-b]pyridine-3-carbaldehyde (Compound XX-1) 1.98 g (10 mmol) and purified on Buch silica gel column chromatography (chloroform:methanol=98:2 to 95:5) to obtain the title compound 996 mg (30%).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1.C(Br)C(C1C=CC=CC=1)=O.[CH2:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH3:24]>N1C=CC=CC=1>[Br-:9].[CH2:8]([N+:28]1[CH:29]=[CH:30][C:25]([CH2:23][CH3:24])=[CH:26][CH:27]=1)[C:7]([C:6]1[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=1)=[O:10]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1ccncc1
Agent: O=C(CBr)c1ccccc1
Solvent: c1ccncc1
Product: CCc1cc[n+](CC(=O)c2ccccc2)cc1
Product: [Br-]

Procedure:
Employing the procedure of Example I but replacing 4-methoxyphenacyl bromide with a substantially equimolecular amount of phenacyl bromide and replacing pyridine with a substantially equimolecular amount of 4-ethylpyridine there is obtained N-(phenacyl)4-ethyl-pyridinium bromide, a white solid melting at 236-238° C., and which is soluble in water.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-:22].[Na+]>C1COCC1>[OH:22][C:17]1[N:18]=[CH:19][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)=[N:15][CH:16]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2cnc(O)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 120 °C
Yield: 70.4 %

Procedure:
To a mixture of (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (100 mg, 0.286 mmol) in THF was added 1 N NaOH solution (1.43 mL, 1.43 mmol). The reaction was heated at 120° C. for 1 h under microwave irradiation. The solvent was removed. The residue was added water and acidified with HCl solution to give the title compound (52 mg) as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(NC(C)C)(C)C.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>ClCCl>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1cccs1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COCCOCOCCc1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
15.0 g of 2-thiopheneethanol was dissolved in 350 mL of dichloromethane, and 30.2 g of diisopropylamine was added thereto. The resulting mixture was cooled to 0° C. and 17.5 g of 2-methoxyethoxymethyl chloride was added thereto. The resulting mixture was stirred for 2 hours and heated to reflux for 2 hours. The reaction product solution was cooled and concentrated by evaporation under reduced pressure. To the residue, 200 mL of water and 250 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 700 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.5 g (yield of 85%) of the title compound as a colorless oil.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([O:16][CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[CH3:17][O:16][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(C)cc1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(C)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 41 %

Procedure:
2-Hydroxy-3-[methoxy-(4-methylbenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 59-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (41% yield); mp 150–152° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.4 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.78 (3H, s, OCH3), 4.21 (2H, s, NCH2), 4.91 (2H, s, NCH2), 7.22 (2H, d, J=8 Hz, aromatics), 7.28 (2H, d, J=8 Hz, aromatics), 11.7 (1H, broad s, OH). Anal. calcd for C15H18N2O4: C, 62.05; H, 6.24; N, 9.65. Found: C, 61.91; H, 6.30; N, 9.56.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][C@H:27]1[O:32][CH2:31][CH2:30][NH:29][C@@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][O:32][C@H:27]([CH3:26])[C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 51.7 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.85 g, 1.9 mmol) was reacted with (2R,3S)-2-methylmorpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.5 g, 52%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C=[O:2].[CH2:3]([OH:10])[C:4]1C=C[CH:7]=[CH:6][CH:5]=1>>[CH:4]([CH:3]=[O:10])=[O:2].[CH:7](=[O:2])[CH2:6][CH2:5][CH2:4][CH:3]=[O:10]
Reactant: C=O
Reactant: OCc1ccccc1
Product: O=CC=O
Product: O=CCCCC=O

Procedure:
It is apparent that simply heating 100% Polymer H at 60° to 95° C for more than 1 hour is not enough to achieve insolubility in 100% benzyl alcohol, but other tests with 4% benzyl alcohol showed that Polymer H crosslinked by heating was not soluble and could be used successfully for making a weak pod seal. Reaction with formaldehyde causes crosslinking and the product is insoluble but swells in 100% benzyl alcohol. Glyoxal and glutaraldehyde give tightly crosslinked products that are insoluble and swell very little in 100% benzyl alcohol. At the low concentration of benzyl alcohol in a photographic developer, these crosslinked compositions formed by heating, or those containing the hardeners and crosslinkers formaldehyde, glyoxal, ethylene diamine, and glutaraldehyde are acceptably resistant to solution.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](CN)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27](OCC)(=O)[CH3:28].[CH3:33][N:34]([CH3:37])[CH:35]=[O:36]>>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:33][N:34]5[CH2:37][CH2:28][CH2:27][C:35]5=[O:36])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 0 °C

Procedure:
Under ice cooling, N,N′-carbonyldiimidazole (160 mg) was added to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3) in dimethylformamide (5 ml) and the resultant mixture was stirred for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound (140 mg) as an oil. This oil was then crystallized from ethyl acetate by using oxalic acid (28 mg) to give the oxalate (150 mg) of the title compound as a white powder (yield: 65%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH3:2].CC1NC2C=CC=CC=2N=1.C(C(CCCC)CBr)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[SH:45].[S]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[S:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=1)[CH3:2]
Reactant: CCCCC(CC)Cn1c(C)nc2ccccc21
Reactant: Nc1ccccc1S
Agent: CCCCC(CC)CBr
Agent: Cc1nc2ccccc2[nH]1
Agent: [S]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3s2)nc2ccccc21

Procedure:
48.8 g (0.2 mol) of 1-(2-ethylhexyl)-2-methylbenzimidazole (prepared by the alkylation of 2-methylbenzimidazole and 2-ethylhexyl bromide under phase transfer conditions), 25 g (0.2 mol) of o-aminothiophenol and 19.2 g (0.6 mol) of sulphur in 200 ml of pyridine are heated for 18 hours under reflux. Then the pyridine is distilled off and the remaining residue is dissolved by heating in 80 g of ethanol. After cooling, 55.2 g (76% of theory) of the product, which, according to its melting point and HPLC and UV analysis, is identical to the compound obtained in Example 18 by route A, are precipitated.
Reaction SMILES: [Na+].[N:2]1([CH2:22][C:23]([O-:25])=[O:24])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]([O-:17])=[O:16])[CH2:7][CH2:6][N:5]([CH2:18][C:19]([O-:21])=[O:20])[CH2:4][CH2:3]1.[Na+].[Na+].CC1(C)[O:36][CH2:35][CH:34]2[CH:32]([O:33]2)[CH2:31][O:30]1.[Gd:38]>>[CH2:4]1[N:5]([CH2:18][C:19]([O-:21])=[O:20])[CH2:6][CH2:7][N:8]([CH2:14][C:15]([O-:17])=[O:16])[CH2:9][CH2:10][N:11]([CH:34]([CH:32]([OH:33])[CH2:31][OH:30])[CH2:35][OH:36])[CH2:12][CH2:13][N:2]([CH2:22][C:23]([O-:25])=[O:24])[CH2:3]1.[Gd+3:38]
Reactant: [Gd]
Reactant: O=C([O-])CN1CCNCCN(CC(=O)[O-])CCN(CC(=O)[O-])CC1
Reactant: CC1(C)OCC2OC2CO1
Agent: [Na+]
Product: O=C([O-])CN1CCN(CC(=O)[O-])CCN(C(CO)C(O)CO)CCN(CC(=O)[O-])CC1
Product: [Gd+3]

Procedure:
The solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt is directly reacted, as described in EP 448191, with 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane to give the alkylated product, which can, easily be complexed with gadolinium to give the final Gadobutrol.