Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH2:27])[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[F:39][C:40]([F:46])([F:45])[S:41](O)(=[O:43])=[O:42].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH:27][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3N)ccc2c1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3NS(=O)(=O)C(F)(F)F)ccc2c1

Procedure:
2-{6-[(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3yl)methyl]quinolin-2-yl}aniline (8.73 g, 21.4 mmol) prepared by the method disclosed in Japanese Patent Unexamined Publication No. 6-80664, triethylamine (6.0 ml, 42.8 mmol) and chloroform (87 ml) were mixed and stirred. While cooling on an ice-bath, a solution of anhydrous trifluoromethanesulfonic acid (3.6 ml, 21.4 mmol) in chloroform (36 ml) was added dropwise over 50 minutes. After stirring for 10 minutes, 2M acetic acid (123 ml) was added dropwise under ice-cooling. The solution was partitioned and the organic layer was washed twice with ion exchange water (123 ml), once with 2% aqueous hydrogencarbonate solution (123 ml) and once with ion exchange water (123 ml) to give a crude solution of N-{2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}phenyl}trifluoromethanesulfonamide in chloroform. To this solution was added ethanol (60 ml), and the mixture was heated to a bath temperature of 90-115° C. to distill away 176 ml thereof. After standing still overnight at 0° C., the precipitated crystals were collected by filtration. The crystals were washed 3 times with ethanol (10 ml) and dried under reduced pressure. Of the obtained crystals (8.48 g), 8.36 g was taken. Thereto were added ethyl acetate (425 ml) and ethanol (175 ml), and the mixture was heated to distill away 325 ml thereof. The reaction mixture was stood still at room temperature and the precipitated crystals were collected by filtration. After washing 3 times with ethanol (10 ml), the crystals were dried under reduced pressure to give 6.36 g of crystals. This recrystallization step was repeated to give 5.52 g of N-{2-{6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]quinolin-2-yl}phenyl}trifluoromethanesulfonamide as yellow crystals, melting point 252.0° C.
Reaction SMILES: C[NH:2][C:3]1[CH:8]=CC=C[CH:4]=1.[F:9][C:10]([N:13]=[C:14]=[O:15])([F:12])[F:11].[C:16]1(C)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:2]([CH:3]([CH3:8])[CH3:4])[C:14]([NH:13][C:10]([F:12])([F:11])[F:9])=[O:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1
Reactant: O=C=NC(F)(F)F
Reactant: CNc1ccccc1
Product: CC(C)N(C(=O)NC(F)(F)F)c1ccccc1

Procedure:
A solution of N-methylaniline (10.7 grams; 0.1 mol) in toluene (100 ml) is charged into a glass reaction flask equipped with stirrer, thermometer and gas inlet tube. Trifluoromethyl isocyanate (11.1 grams; 0.1 mol) is slowly bubbled into the reaction medium with vigorous stirring and sufficient cooling to keep the temperature of the reaction mixture below about 50° C. After the addition is completed the reaction mixture is stirred for an additional period of about 1 hour. After this time the toluene is stripped from the reaction mixture under reduced pressure. The residue is then recrystallized to yield N-phenyl-N-isopropyl-N'-trifluoromethyl urea.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][CH:13]1[C:26](=[O:27])[N:15]2[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]12.[CH3:28][C:29]([CH3:37])([CH3:36])[C:30]([O:32][CH:33](I)[CH3:34])=[O:31].[C:38]([NH:57][C:58]1[S:59][CH:60]=[C:61](/[C:63](=[N:67]/[O:68][C:69]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)/[C:64](Cl)=[O:65])[N:62]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:22][O:21][CH2:20][C:17]1[CH2:18][S:19][C@@H:14]2[CH:13]([NH:12][C:64](=[O:65])/[C:63](/[C:61]3[N:62]=[C:58]([NH:57][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[S:59][CH:60]=3)=[N:67]\[O:68][C:69]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)([C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:26](=[O:27])[N:15]2[C:16]=1[C:23]([O:25][CH:33]([O:32][C:30](=[O:31])[C:29]([CH3:37])([CH3:36])[CH3:28])[CH3:34])=[O:24]
Reactant: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: O=C(Cl)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
9.5 ml (64 mmol) of DBU are slowly added to a suspension of 14.0 g (57 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 160 ml of anhydrous methylene chloride at 0° C. and the mixture is subsequently stirred at 0° C. for 30 minutes. 20.8 g (81 mmol) of 1-iodoethyl 2,2-dimethylpropionate are then added and the mixture is stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature in the course of 30 minutes. After renewed cooling to 0° C., the crude 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetyl chloride (≃ 54 mmol), dissolved in 100 ml of methylene chloride, is added dropwise and the mixture is then stirred at 0° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The mixture is washed successively with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The crude product is purified by chromatography on silica gel (35-70 μm) (column: 50 cm×8.5 cm, toluene/ethyl acetate=5/1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:3]=1[NH2:12].[CH2:13]([C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:12][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[CH2:13][CH3:14])=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]=[CH:6][N:7]=1
Reactant: Nc1c(Cl)ncnc1NC1CC1
Reactant: CCc1ncccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ncccc1C(=O)Nc1c(Cl)ncnc1NC1CC1
Temperature: 0 °C

Procedure:
6-Chloro-N-cyclopropylpyrimidine-4,5-diamine (cf. Journal of Combinatorial Chemistry (2003), 5(5), 653-659) (3.0 g, 16.2 mmol) was initially charged in a mixture of methylene chloride (12.20 ml) and pyridine (3.94 ml). The suspension was cooled to 0° C., and solid 2-ethylnicotinoyl chloride (1.2 eq) was added. The reaction mixture was allowed to warm to room temperature and stirred until the reaction had gone to completion. 10 ml of methylene chloride were then added, the suspension turning into a solution. About 10 ml of semisaturated NaHCO3 solution were added to the organic phase whilst the mixture was stirred vigorously in a flask using a magnetic stirrer; poorly soluble crystals (product) precipitated and were filtered off with suction, washed 3× with a little water and 3× with n-heptane and dried.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH3:26])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:21]C)=[C:14]([CH:23]([CH3:25])[CH3:24])[CH:13]=1)=[O:11].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH3:26])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([OH:21])=[C:14]([CH:23]([CH3:24])[CH3:25])[CH:13]=1)=[O:11]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 72 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (0.973 g, 2.01 mmol) and 1M boron tribromide/CH2Cl2 (4.23 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.679 g (72%) of the title compound. 1H NMR (DMSO-d6) δ1.13 (d, 12H), 1.82 (s, 3H), 2.18 (s, 3H), 3.31 (septet, 2H), 3.94 (s, 2H), 7.12-7.17 (m, 2H), 7.30 (dt, 1H), 7.42 (s, 2H), 7.52 (d, 1H), 9.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:25]([O:29][C:30](=[O:33])[CH:31]([C:21]([C:16]1[C:17]([O:19][CH3:20])=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:22])[NH2:32])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(=O)C(N)C(=O)OC(C)(C)C)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid obtained by Example 234 and 258 mg of glycine ter-butyl ester hydrochloride were dissolved in 20 mL of N,N-dimethylformamide, and 0.871 mL of diisopropylethylamine and 235 mg of 1-hydroxybenzotriazole were added, and stirred at room temperature for 10 minutes. After cooling to 0° C., 491 mg of WSC hydrochloride was added, and stirred overnight at room temperature. After adding ice water to stop the reaction, the solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 547 mg of the title compound as pale green crystals.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O=S(Cl)Cl.Cl.[CH3:22][NH:23][O:24][CH3:25].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:22][N:23]([O:24][CH3:25])[C:12](=[O:14])[CH2:11][C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([CH3:16])[CH3:15]
Reactant: CNOC
Reactant: CC(C)(CC(=O)O)c1cccc2c1OCC2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)CC(C)(C)c1cccc2c1OCC2
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-(2,3-Dihydrobenzofur-7-yl)-3-methylbutanoic acid (800 mg) in CH2Cl2 (10 mL) was treated with SOCl2 (0.315 mL) at 0° C. After 30 minutes, N,O-dimethylhydroxylamine hydrochloride (421 mg) in pyridine (1.5 mL) was added to the green mixture at 0° C. After another 30 minutes, 15 mL of 2 M HCl was added. The organic phase was separated and the aqueous layer was extracted with three 20 mL portions of CH2Cl2. The combined organic phases were dried over magnesium sulfate. The solvent was removed to yield 950 mg (99%) of 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanoic acid N,O-dimethylhydroxylamide as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:24]([O-:26])=[O:25])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[C:8]([O:10]CC=CC(C)(C)C)=[O:9].[CH:28]([O-])=O.[NH4+].C1(P([C:45]2[CH:50]=[CH:49]C=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.[Pd]>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:24]([OH:26])=[O:25])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[C:8]([O:10][C:50]([CH3:49])([CH3:45])[CH3:28])=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1=C(C(=O)[O-])C(c2ccccc2)C(C(=O)OCC=CC(C)(C)C)=C(C)N1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC1=C(C(=O)O)C(c2ccccc2)C(C(=O)OC(C)(C)C)=C(C)N1

Procedure:
A sample of (+) tertbutyl,allyl 2,6-dimethyl-4phenyl-1,4-dihydropyridine-3,5-dicarboxylate is treated in dioxane with 10% Pd on C, ammonium formate and triphenylphospine to give (+)-tertbutyl 2,6-dimethyl-4-phenyl-5-carboxy-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[C:10]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[CH:9]=1.C1C=CC2N(O)N=[N:44]C=2C=1.C(Cl)CCl.N>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH2:44])=[O:16])=[C:10]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][CH:25]([OH:30])[C:26]([F:28])([F:29])[F:27])[C:20]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[N:19]2)[CH:9]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
43 mg (0.08 mmol) of the compound from Example 132 were initially charged in 1 ml of DMF, and 14 mg (0.10 mmol) of HOBt and 19 mg (0.10 mmol) of EDC were added. After 10 min of stirring at RT, 0.41 ml (0.20 mmol) of ammonia solution (35% strength in water) was added, and the mixture was stirred at RT for 16 h. Under reduced pressure, the reaction solution was then freed of excess ammonia, about 3 ml of water were added and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 1:3→1:5). This gave 19 mg (42% of theory) of the target compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54][C:55](O)=[O:56])=[CH:46]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:55](=[O:56])[CH2:54][C:47]3[C:48]4[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:45]([CH3:44])[CH:46]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c2ccccc21
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-methyl-3-indoleacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 5:95) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(1-methyl-1H-indol-3-yl)-acetamide (0.8 g, 83%) as a yellow solid: mp 231-233° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.53 min. (98%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.54-2.63 (m, 2H), 2.83-2.91 (m, 1H), 3.62 (s, 2H), 3.73 (s, 3H), 4.70 (d, J=5.9 Hz, 2H), 5.10-5.16 (dd, J=5.2 and 12.7 Hz, 1H), 6.99-7.04 (dd, J=7.1 and 7.9 Hz, 1H), 7.12-7.17 (dd, J=7.1 and 7.9 Hz, 1H), 7.21 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.54-7.79 (m, 4H), 8.47 (t, J=5.9 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 32.23, 32.34, 37.86, 48.83, 107.82, 109.50, 118.39, 118.78, 121.07, 121.79, 127.06, 127.47, 128.27, 131.46, 133.19, 134.54, 136.53, 139.38, 166.91, 167.45, 169.77, 171.15, 172.71; Anal. Calcd. for C25H22N4O5: C, 65.49; H, 4.84; N, 12.22. Found: C, 65.11; H, 4.54; N, 12.05.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])C=O.N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCC(C)C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCC(C)/C=C/C(=O)O
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Malonic acid (44 g, 0.42 mol), 2-methylpentan-1-al (14 g, 0.14 mol) and piperidine (1.7 ml) were suspended in 85 ml pyridine and heated under reflux. Gas formation was observed which ceased after two hours. Heating was continued for 1 hour. The cooled reaction mixture was poured into 2M hydrochloric acid (200 ml) after which two phases were obtained which were separated in a separating funnel. The aqueous phase was extracted once with dichloromethane (60 ml). The organic phases were combined and the solvent removed under reduced pressure. The residue was purified by column chromatography (pre-packed silica column, gradient of pentane/ethyl acetate). 9.3 g (0.065 mol, 47% yield) of (E)-4-methyl-hept-2-enoic acid were obtained as a solid. NMR (1H, CDCl3, 300 MHz): 11.86 (s, 1H), 7.00 (dd, 1H), 5.79 (d, 1H), 2.35 (m, 1H), 1.35 (m, 4H), 1.06 (d, 3H), 0.89 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH2:13][CH2:14]O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[Br-:17].C[S+](C)[Br:20]>CN(C)C=O.[Ag]>[BrH:20].[N+:1]([C:4]1[N:5]([CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: [Br-]
Reactant: C[S+](C)Br
Reactant: O=[N+]([O-])c1nccn1CC(O)CNCCO
Agent: [Ag]
Solvent: CN(C)C=O
Product: Br
Product: O=[N+]([O-])c1nccn1CC(O)CNCCBr
Temperature: 50 °C
Reaction time: 12 h
Yield: 18.2 %

Procedure:
A mixture containing 1-(2-nitro-1-imidazolyl)-3-(2-hydroxyethylamino)-2-propanol (RSU-1137) prepared as described by Silver et al. [Silver, A. R. J., McNeil, S. S., O'Neill, P., Jenkins, T. C. and Ahmed, I., Biochemical Pharmacology 1986 35 3923-3928] (2.30 g, 10.0 mmol) and dimethylbromo-sulphonium bromide (2.22 g, 10.0 mmol) prepared by the method of Furukawa et al. [Furukawa, N., Inoue, T., Aida, T. and Oae, S., J. Chem. Soc. Chem. Commun. 1973 212] in N,N-dimethylformamide (20 cm3) was stirred at 50° C. for 12 hours. The reaction mixture was concentrated in vacuo, digested in ethanol (10 cm3) and separated by preparative column chromatography using silica gel as the stationary phase and chloroform-methanol (9:1 v/v) as eluant. 1-(2-Nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol hydrobromide (0.68 g, 18.2%) was obtained as a yellow solid, m.p. 148.5°-150.5° C. after treatment of the eluate with ethereal hydrogen bromide.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2nccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-dichloropyrazine (470 mg, 3155 μmol) was combined with 4-aminophenol (344 mg, 3155 μmol) and cesium carbonate (1233 mg, 3786 μmol) in DMSO (5 ml) and heated to 70 C. After 3 hours, the mixture was cooled to room temperature, transferred to a separatory funnel rinsing with ethyl acetate and water, the layers were separated and the aqueous was extracted with ethyl acetate (3×). The combined organics were rinsed with brine, dried over sodium sulfate, filtered and concentrated to yield a brown solid which was carried forward without purification.
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:14]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:14]1([C:18]([NH:1][C@H:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)C[C@H](N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)C1CCC1)c1ccccc1

Procedure:
To a solution of the amino ester from Example 6, Step A (4.2 mmol, 896 mg) and cyclobutanecarboxylic acid (5.0 mmol, 476 μL) in 10 mL of DCM containing N,N-diisopropylethylamine (12.5 mmol, 2.17 mL) was added 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (5.0 mmol, 958 mg). After 16 h the reaction mixture was washed with H2O (10 mL), 1 M citric acid (10 mL) and saturated NaHCO3 (10 mL). The organic phase was dried with MgSO4 and the solvent removed under reduced pressure to afford the product as a white solid. MS (ESI): m/z 485 (M+H). HPLC B: 1.58 min.
Reaction SMILES: [CH2:1]([Cl:6])/[CH:2]=[CH:3]/[CH2:4][Cl:5].[CH3:7][N:8]([CH3:10])[CH3:9].CC(=O)CCCC>O>[Cl-:5].[Cl:6][CH2:1][CH:2]=[CH:3][CH2:4][N+:8]([CH3:10])([CH3:9])[CH3:7]
Reactant: ClC/C=C/CCl
Reactant: CN(C)C
Solvent: CCCCC(C)=O
Solvent: O
Product: C[N+](C)(C)CC=CCCl
Product: [Cl-]
Yield: 93.5 %

Procedure:
About 125 parts 1,4-dichlorobutene-2 and 60 parts trimethylamine are mixed with 700 parts 2-hexanone in a stainless steel pressure reactor. The mixture is allowed to react for 5 hours at a temperature of about 75°C. to about 80°C. Next, 60 parts of water are added to the cooled reaction mixture. This mixture yields about 93.5% 4-chloro-2-butenyltrimethylammonium chloride. The 2-hexanone is removed either by vacuum distillation or separated by decantation from the reaction mixture. About 95% of the 2-hexanone is recovered for reuse.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH2:10][CH2:9][CH2:8]3)=[O:6])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Product: O=C(CCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1cccc(CN[C@H]2CCCc3ccccc32)c1Cl

Procedure:
2,3-Dichlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.