Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:23]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:43].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:43][C:9]1[C:8]2[N:23]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:29])[CH3:30])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(N4CCCC4=O)ccc3c2n1CCCOC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(N4CCCC4=O)ccc3c2n1CCCOC(C)C
Temperature: 2 °C
Reaction time: 16 h

Procedure:
1-[2-Ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one (0.38 g) was dissolved in chloroform (10 mL). 3-Chloroperoxybenzoic acid (60% pure, 0.37 g) was added in one portion and the mixture was allowed to stir for 16 hours. Ammonium hydroxide (10 mL) was added and the biphasic mixture was cooled to 2° C. with an ice/water bath. Benzenesulfonyl chloride (0.22 mL) was added and the reaction was stirred for 3 hours. The layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with water and saturated aqueous sodium chloride; dried over anhydrous sodium sulfate; filtered and concentrated under reduced pressure. The residue was purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge. The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 73:27. Fractions containing product were combined and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to afford 0.14 g of 1-[4-amino-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one as a white solid, mp 165-167° C.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:28]#[N:29])[C:10]([CH3:27])=[C:11]([C:21]4[CH2:25][CH2:24][CH:23](O)[CH:22]=4)[C:12]=3[N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.Cl.C(O)C>C(O)C.C(OCC)C>[CH:21]1([C:11]2[C:12]([N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:19])[CH3:20])[CH2:14]3)=[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]3=[C:9]([C:28]#[N:29])[C:10]=2[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22]1
Reactant: Cc1c(C2=CC(O)CC2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1c(C2C=CC=C2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Reaction time: 4 h
Yield: 78839.7 %

Procedure:
2-Cyclopropyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-(3-hydroxycyclopent-1-enyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-306) (83 mg, 0.21 mmol) was dissolved in ethanol (0.85 ml) and diethyl ether (1.7 ml), and at room temperature, 1 M hydrochloric acid/ethanol solution (222 μl, 0.22 mmol) was added. After stirring at the same temperature for 4 hours, the solvent was evaporated away under reduced pressure. Ether was added to the residue, and this was concentrated under reduced pressure. This operation was repeated once again. Ether was added to the residue, followed by sonication, and the solvent was removed with a pipette. The residue was dried at 60° C. under reduced pressure for 2 hours to obtain the entitled compound (62 g, 65%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20](O)=[O:21]>C1(C)C=CC=CC=1>[CH:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][CH:17]=1)=[O:21]
Reactant: O=CO
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2ccc(NC=O)cc2)cc1OC
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (9.9 g, 38.9 mmole) is dissolved in toluene (125 ml) containing formic acid (5.0 g, 108 mole) and refluxed for one hour. The reaction mixture is cooled to room temperature and evaporated to dryness. Recrystallization of the residue from toluene affords 11.0 g (82%) of N-formyl-4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine, mp 128°-130° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]
Reactant: NN
Reactant: Fc1ccccc1-c1cc(Cl)nc2ccc(Cl)cc12
Solvent: O
Product: NNc1cc(-c2ccccc2F)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-(o-fluorophenyl)quinoline is reacted with hydrazine hydrate at reflux to give 6-chloro-4-(o-fluorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1>CN(C)C=O.C(OCC)(=O)C.C(OCC)C.CCCCCC>[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:40][C:41](=[O:42])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]5[CH2:27][CH2:26][CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:28][CH:29]=2)=[O:39])=[CH:35][CH:36]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a solution of 4-[2-(azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (32.4 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.98 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (1.5 ml) and hexane (1.5 ml). The solid was filtered off and dried under aeration to provide the titled compound (9.2 mg, 19.6%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:27]2[S:28][C:24]([CH3:23])=[CH:25][N:26]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 5-methyl-thiazol-2-ylamine (28 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-thiazol-2-yl)-acetamide (74 mg, 69%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H20ClN3O4S2 [M+] 441.06, found 442 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.66 (m, 4 H, 2×CH2), 1.89 (m, 4 H, 2×CH2), 2.45 (d, J=1.2 Hz, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.93 (m, 1 H, OCH), 7.15 (brq, 1 H, Ar), 7.59 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.70 (d, Jm=1.5 Hz, 1 H, Ar), 8.21 (d, Jo=8.2 Hz, 1 H, Ar), 10.03 (s, 1 H, NH).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].Cl>[OH-].[Na+]>[C:1]1([S:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNS(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Benzenesulphonyl chloride (10 ml) was added to a stirred solution of 6-aminocaproic acid (8.8 g) in 10% sodium hydroxide solution (50 ml) over 30 minutes. The solution was stirred for 1 hour, acidified with dilute hydrochloric acid and the precipitate was collected by filtration. Recrystallisation from chloroform yielded 6-(benzenesulphonamido)hexanoic acid (10.5 g) as white prisms. m.p. 119°-120° C.
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=[C:42]2[CH:51]([O:53][CH2:54][CH:55]=[C:56](C)[CH3:57])[CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.BrCC=C(C)C>[CH2:54]([O:53][CH:51]([C:42]1[C:41]2[C:46](=[CH:47][CH:48]=[C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[O:32][CH3:31])[CH:40]=2)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=1)[CH3:52])/[CH:55]=[CH:56]/[CH3:57]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCC=C(C)C)=CC(C)(C)N2
Agent: CC(C)=CCBr
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 32.7 %

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-methylbut-2-enyloxy)ethyl]-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (96 mg) was treated with 450 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 50 μL of 4-bromo-2-methyl-2-butene to give the alkylated product, which was deprotected to yield 14.5 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([CH3:12])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(NCc2ccc(N(C)C)cc2)cc1C
Yield: 55.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (1.5 g) and 3,4-dimethylaniline (1.2 g) as starting materials, [(4-dimethylaminophenyl)methyl](3,4-dimethylphenyl)amine (1.4 g) was obtained. melting point: 73–75° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH2:32][CH2:33][CH3:34])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[OH:25][CH2:24][C@H:23]([NH:22][S:17]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[C@@H:26]1[CH2:27][C@@H:28]([CH2:32][CH2:33][CH3:34])[C:29](=[O:31])[O:30]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 2 h
Yield: 52 %

Procedure:
23.9 g of triethylamine (237 mmol) and 26.7 g of O-nitrobenzenesulfonyl chloride (120 mmol) were added to a solution of (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-propyldihydrofuran-2-one hydrochloride obtained in the above reaction in a mixed solvent of tetrahydrofuran (350 ml) and water (35.0 ml) at 0° C. The mixture was stirred at the same temperature for two hours and further stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and 500 ml of water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 30 ml of diisopropyl ether and 30 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 14.6 g of the title compound (total yield over two steps: 52%).
Reaction SMILES: [IH:1].Cl[C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][N:4]=1.[OH-].[Na+]>>[I:1][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][N:4]=1
Reactant: I
Reactant: Clc1cc(-c2cccs2)ncn1
Agent: [Na+]
Agent: [OH-]
Product: Ic1cc(-c2cccs2)ncn1
Reaction time: 20 h
Yield: 93.6 %

Procedure:
Aqueous solution of HI (63.5 g, 496.5 mol, 13.9 equiv) was charged to 4-chloro-6-thiophen-2-yl-pyrimidine (3, 7.0 g, 35.6 mmol) and stirring was continued for 20 h. Reaction mixture was then made slightly alkaline (pH˜10) by using 5% NaOH solution. Subject compound was precipitated out, filtered, washed well with distilled water and dried under vacuum to yield 9.6 g of 4 (Yield=94.1%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[CH:32]=[N:33][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:25])([F:26])[F:27])[CH:3]=2)[CH:35]=1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)c2)c1
Yield: 50.4 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0.20 g) and dimethylformamide (25 ml), the product (0.47 g) was obtained as a colorless amorphous solid, MS, m/z: 437.3 (M+H)+, 873.2 (2M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]O)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCOCCOc1ccccc1CO
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 151.5 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-(2-propoxyethoxy)benzyl alcohol (0.63 g) and triphenylphosphine (782 mg) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene, 1.36 ml), and the resulting mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2) to obtain crude methyl 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.04 g).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[N:3]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[N:2]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: CCOC(=O)CBr
Reactant: c1c[nH]nn1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1ccnn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
129.2 g (5.6 mmol) of sodium are added slowly to 4.0 litres of ethanol. 400.0 g (5.6 mol) of 1,2,3-1H-triazole are then added, and 623 ml (938.2 g, 5.6 mol) of ethyl bromoacetate are added dropwise at an internal temperature of 20-25° C. The mixture is stirred at RT for 48 h. The precipitated solid is filtered off, the ethanol is removed under reduced pressure and the mixture is filtered again. The residue is taken up in ethyl acetate, filtered, again concentrated under reduced pressure and purified by distillation on a 30 cm column. The product is obtained at a bath temperature of 140° C., a head temperature of 60-115° C. and a pressure of 1 mbar. Yield: 440.0 g (50% of theory)
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].C(OC(Cl)=O)=C>>[CH3:4][C:2]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[S:8][CH:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1csc(C2CCN(Cc3ccccc3)CC2)n1
Agent: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.8 g 4-(4-(1,1-Dimethylethyl)-2-thiazolyl)-1-phenylmethyl-piperidine, 2 g K2CO3 and 50 ml 1,2-dicnloroethane are treated dropwise at -5° under stirring with 3.2 g chloroformic acid vinyl ester. The mixture is stirred 2 hours at room temperature and evaporated. The residue is partitioned between ethyl ether and water. The ether phase is evaporated and the residue dissolved in 30 ml metnanol and 30 ml 20% aqueous hydrochloric acid. The mixture is heated 1 hour at 60 and evaporated. The residue is partitioned between aqueous NaOH and ether. The etner phase is treated with maleic acid to yield the hydrogenmaleinate of the title compound, m.p. 141°-142° (ethanol/ether).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.[O:22]1[C:26]2([CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[O:25]C[CH2:23]1>O1CCCC1.CCCCCC.O>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:23][O:22][C:26]4([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:25]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(c1ccccc1)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C2OC3(COC4(CCCCC4)O3)c3ccccc32)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a cooled (-50° C.) stirred solution of 27.7 g of 2-bromobenzhydryl methyl ether in 80 ml of dry tetrahydrofuran is added dropwise under nitrogen 60 ml of 2.4 M n-butyllithium in hexane. The mixture is stirred for 2 hours and a solution of 15.9 g of 1,4-dioxaspiro[4.5]decan-8-one in 50 ml of dry tetrahydrofuran is added dropwise, maintaining the temperature at -40° to -30° C. The mixture is stirred overnight at -70° to +10° C., diluted with 100 ml of water and extracted with 100 ml of dichloromethane. The organic phase is washed with water (2×50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. A solution of the residue in 400 ml of ethanol is stirred with 50 ml of hydrogen bromide/ether at room temperature for 3 hours. The solvent is removed under reduced pressure and the remaining oil crystallizes from 100 ml of methanol to give 39.6% of product, mp: 130°-132° C.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=O)O.N[C@H:12](C(O)=O)CC(=O)O>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[C@H:3]([CH2:4][CH3:5])[CH3:12]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
A8, Glu or Asp;
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:7]=1)=[O:5])C>[OH-].[Na+].CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:8]2[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:6]([C:4]([OH:5])=[O:3])=[N:7]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2cc([N+](=O)[O-])c(C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.2 %

Procedure:
A mixture of 1-(4-methoxy-benzyl)-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (15.9 g, 52 mmol) in 2 M aqueous NaOH/MeOH (1:1, 400 ml) was stirred at ambient temperature for 14 h. Volatile materials were removed in vacuo, the residue dissolved in EtOAc (200 ml), water (100 ml) added and the mixture taken to pH 3 using 1M aqueous HCl. The layers were separated and the organic portion washed with saturated aqueous sodium hydrogen carbonate. EtOAc was added to the aqueous layer which was acidified to pH 3-4, and the combined organic portions dried (MgSO4) and reduced in vacuo to give 1-(4-methoxy-benzyl)-4-nitro-1H-pyrazole-3-carboxylic acid (13 g, 86%) as a white solid. (LC/MS: Rt 2.63, [M+H]+ 292).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:11][CH2:10]1.Cl.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl.CO.O.C([O-])([O-])=O.[K+].[K+]>[Br:31][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[N:29]=[CH:28][CH:27]=[CH:26][C:20]=3[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:13][CH2:14]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)ccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
2-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.21 g, 0.53 mmol), prepared as in Example 21, was dissolved in methylene chloride and the solution was treated with excess hydrochloric acid in methanol and concentrated under reduced pressure. The residue was dissolved in 6 mL of DMF and N-bromosuccinimide (0.101 g, 0.57 mmol) was added. The mixture was stirred at room temperature for approximately 24 hours, diluted with water and basified with K2CO3. The basified mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 2-{3-[4-(4-bromo-2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.19 g, 0.40 mmol) as an oil.