Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:22])=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=3[CH3:18])[C:11](=[O:23])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2)=[C:4]([CH3:29])[CH:3]=1.[N+:30]([O-])([O-:32])=[O:31].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([N+:30]([O-:32])=[O:31])=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:22])=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=3[CH3:18])[C:11](=[O:23])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2C)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2C)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Ethyl 1-(4-fluoro-2-methylphenyl)-6-fluoro-8-methyl-7-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.1 g) was added to concentrated sulfuric acid (10 ml), and potassium nitrate (330 mg) was added to the mixture under ice cooling. The resultant mixture was stirred at room temperature for 4 days. The reaction mixture was poured into ice water and extracted with chloroform. A chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (1.1 g) as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>>[C:1]([NH:4][C:5]1[S:6][C:7]([Br:18])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1sccc1C(N)=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Nc1sc(Br)cc1C(N)=O
Reaction time: 8 h
Yield: 13.9 %

Procedure:
2-Acetylamino-thiophene-3-carboxylic acid amide (3.89 g, 27.4 mmol) was suspended in the aqueous solution of sodium acetate (2.47 g, 30.1 mmol)(136 mL). Bromine (1.4 mL, 27.4 mmol) was added dropwise to the solution. The resulting solution was stirred under nitrogen overnight. Once the LC-MS showed no remaining starting materials, the reaction mixture was then filtered and washed with water (50 mL). The filtrate was then purified utilizing a Gilson preparative. HPLC to give the above titled compound as a brown solid (1 g, 13.8%). LC-MS [M+H]+ m/z 263.
Reaction SMILES: [CH2:1]1[O:16][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>C(O)(C)C>[CH2:23]([NH:24][CH2:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CC(C)O
Product: CCCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-pentadecene oxide (81.7 g.) and hexamethylenediamine (21 g.) and recrystallization of the resulting product (74.3 g.) from isopropyl alcohol gave N,N'-(1,6-hexylene)-bis[2-hydroxypentadecylamine] (I: R = CH3 (CH2)12, R' = H, X = (CH2)6, Z = H) (m.p. 117.4°-124.0° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH2:4][CH3:5])[CH3:2].Cl.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15][CH:14]=1.C(N(CC)CC)C>O>[CH3:10][CH:9]([NH:11][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[CH:14][CH:15]=1)=[O:24])[CH2:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C(Cl)c1ccnc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CCCC(C)NC(=O)c1ccnc2ccccc12

Procedure:
2-[2'-(5"-nitrofuryl-2")vinyl]quinoline-4-carboxylic acid (α-methyl-δ-diethylaminobutyl)amide was prepared from 1.58 g (0.01 mol.) of diethylamino-4-aminopentane and 3.65 g (0.01 mol.) of 2-[2'-(5"-nitrofuryl-2")vinyl]quinoline-4-carboxylic acid chloride hydrochloride in 50 ml of water in the presence of triethylamine. The process was conducted as described in Example 5.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N+:4]([O-:29])[CH:3]=1.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[CH:11]=[C:2]([F:1])[CH:3]=[N+:4]([O-:29])[C:5]=3[CH:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c2cc(F)c[n+]3[O-])CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(CCn2c(=O)ccc3c2cc(F)c[n+]3[O-])CC1
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl {1-[2-(7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-4-piperidinyl}carbamate (335 mg, 0.824 mmol) was dissolved in DCM (3 mL) and 4M HCl in 1,4-dioxane (0.830 mL (ca. 4 eq.) was added. A further 10 mL DCM was added to disperse the solid, then a further 0.830 mL 4M HCl in 1,4-dioxane was added. The mixture was left at room temperature for 30 minutes, then the solvents were removed under reduced pressure to give title compound as a white solid (315 mg).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]3[C:35]([C:36]=2[NH2:37])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:27]3[CH:28]=[N:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]=3[NH:37][C:1]2=[O:2])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(NC2CCN(Cc3ccccc3)CC2)cnc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
22.6 g (139 mmol) 1,1′-carbonyldiimidazole were added to a solution of 9.0 g (27.1 mmol) N3-(1-benzylpiperidin-4-yl)-quinoline-3,4-diamine in 100 mL DMF. The mixture was heated to 100° C. and stirred for 1.5 h at this temperature. After cooling the reaction mixture it was poured onto 300 mL water. The precipitated solid was filtered off, washed with water and dried at 30° C. i. vac. The residue was triturated with diethyl ether, suction filtered and the solid product was dried i. vac.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:17]=2)=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13]>O1CCCC1>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([NH:4][CH:1]3[CH2:3][CH2:2]3)(=[O:24])=[O:25])[CH:17]=2)=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13]
Reactant: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c(Cl)c1OC(F)F
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)NC3CC3)c2)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.9 g (16 mmol) of cyclopropylamine was added to a solution of 3 g (7.6 mmol) of 4-chloro-3-(4-chloro-3-chlorosulfonylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 25 ml of tetrahydrofuran. The mixture was stirred at room temperature for 4 hours and then concentrated to dryness. The solid residue was washed with a little diisopropyl ether. Yield: 3 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[CH:6][CH:5]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)c1cccc(OS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 32.5 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 1-(3-hydroxy-phenyl)-propan-1-one (2 kg, 13.32 mol) and potassium carbonate (3.681 kg, 26.64 mol) in dichloromethane (20 L), p-toluenesulfonyl chloride (2.8 kg, 14.65 mol) was added at 30-35° C. The reaction mixture was stirred at 30-35° C. for 1 hour. Reaction mixture was diluted with dichloromethane (10 L) and washed with water (2×10 L). Dichloromethane layer separated, dried and solvent distilled off to give title compound. Cyclohexane (10 L) was added to the resulting product at 65-70° C. and stirred for 2 hours. Mixture was cooled to ambient temperature, filtered and dried to give 3.87 kg the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[OH:12]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: COc1ccc(C(O)c2ccccn2)c(Cl)c1Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccccn2)c(Cl)c1Cl

Procedure:
α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol (31.86 g) is dissolved in 600 ml of acetic acid and 100 ml of H2O. Chromic anhydride (11.0 g) is added portionwise over five minutes. After three hours the reaction mixture is poured into H2O and extracted with ether. The combined organic phase is washed well with 10% NaHCO3, then brine and dried. Removal of the solvent under reduced pressure gives a crystalline product of (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone, mp 104°-107° C.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:19](OC(=O)C)(=O)[CH3:20]>C(O)(=O)C>[CH3:19][C:20]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 91 %

Procedure:
15.12 g of 2-(theophyllin-7-yl)-acetamidoxime are heated on water bath for two hours with a mixture of 120 cm3 acetic acid and 8 cm3 of acetic anhydride. The solvent is distilled off and 16.06 g. (91%) of 7-[(5-methyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 135° C. (methanol).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[S:30]([CH2:29][CH2:28][N:19]2[C:18](=[O:17])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:27])(=[O:31])=[O:32])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NCc2nccs2)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Product: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide was prepared by an analogous procedure as described for example 1 i) starting from 217 mg (0.91 mmol) (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amine and 250 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. Purification by flash chromatography on silica gel (eluent: CH2Cl2/MeOH) gave pure 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide as a light yellow foam. Yield: 178 mg MS (ES+): m/e=477.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)[CH:29]=[N:30][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:25][C:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)[CH:29]=[N:30][CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCOc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]([CH2:38][C:39]#[CH:40])[CH3:37].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:40]#[C:39][CH2:38][N:36]([CH3:37])[CH3:35])=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
To a degassed solution of methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (480 mg, 0.818 mmol; prepared as described in example 53), N,N-dimethylpropargylamine (0.175 mL, 1.64 mmol) and diisopropylamine (0.539 mL, 3.85 mmol) in anhydrous tetrahydrofuran (10 mL), bis(triphenylphosphine)-palladium(II) dichloride (29 mg, 0.041 mmol) and copper(I) iodide (13 mg, 0.068 mmol) were added. The reaction mixture was stirred at ambient temperature over night under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [C:1]([NH:9]O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+]>CO>[CH2:1]([NH:9][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NO)c1ccccc1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNCc1ccccc1

Procedure:
13.7 Grams (0.1 mole) of benzhydroxamic acid and 8.8 g (0.1 mole) of chloroacetic acid were dissolved in 60 ml of methyl alcohol. To the resulting solution, 20 g (0.2 moles) of 40% aqueous solution of sodium hydroxide was slowly added dropwise. After completion of the addition, the reaction solution was heated under reflux for 8 hours and subsequently cooled. After distilling of methyl alcohol under vacuum, concentrated hydrochloric acid was added to the remaining aqueous solution so as to adjust pH to 1. Ethyl acetate (50 ml) was added to the solution. The separated organic layer was washed twice with 50 ml of a saturated sodium chloride solution. By distilling off ethyl acetate, benzamidooxyacetic acid (m.p. 144°145° C.) was obtained in an amount of 18.2 g (yield, 93 mol %).
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[C:1]1([CH:7]([NH:9][CH2:10][CH:12]([OH:14])[CH2:13][NH:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)c1ccccc1
Reactant: ClCC1CO1
Product: CC(NCC(O)CNC(C)c1ccccc1)c1ccccc1

Procedure:
The racemate of α-phenylethylamine (1) was used as starting material and condensed with epichlorohydrin in the absence or presence of a solvent to obtain the racemate of 1,3-bis-[(1-phenylethyl)amino]-2-propanol (2) which was then cyclized with cyclizing reagents to give racemic 1,3-oxazolidin-2-one (I). Further reaction with an appropriate acid would give a salt of 1,3-oxazolidin-2-one (I).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].O.N([O-])=O.[Na+].C(Cl)Cl.[BrH:20]>>[Br:20][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: Br
Reactant: N#Cc1ccc(N)cc1C#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Br)cc1C#N
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 4 (24 g, 0.17 mol) was suspended in a stirring solution of 100 ml HBr (48%) and 100 ml of H2O cooled to −10° C. Sodium nitrite (14 g, 0.20 mol) was dissolved in ice water and added dropwise to the solution of 4-aminophthalonitrile. The exothermic reaction was carefully monitored and kept under 0° C. After 2 hours of stirring, the solution was added dropwise to a solution of Cu(I)Br (27 g, 0.18 mol) in 100 ml of HBr (48%) at −3° C. and stirred at 0° C. for 2 hours. To minimize foaming as well as increase the yield, methylene chloride was added to the solution and the reaction was allowed to proceed overnight for at least 24 hours. The organic layer was removed, and the aqueous layer was also extracted with toluene. The combined organic layers were washed with water, Na2S2O3 (saturated aqueous solution), water, brine, water, dried over MgSO4 and evaporated under reduced pressure. 25 g of an orange product were collected (73%). 1H NMR (CDCl3) δ: 7.99 (d, 1H), 7.94-7.91 (dd, 1H), 7.72-7.70 (d, 1H).6 13C{1H}NMR (CDCl3) 136.68, 136.42, 134.44, 128.19, 117.39, 114.76, 114.65, 114.04 ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](#[N:29])[CH3:28].CO>C(OCC)(=O)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:8][CH2:7][CH2:6][CH2:11][CH2:28][CH2:27]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: CC#N
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc2c(-c3ccc(OCCCN4CCCCCC4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, hexamethyleneimine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=366.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][NH:37][CH3:38]>>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][N:37]([C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1)[CH3:38]
Reactant: CNCCN(C)C
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(N(C)CCN(C)C)c1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-dimethylaminoethyl)-N-methylamine to give the title compound in 44% yield; NMR Spectrum: (DMSOd6) 2.17 (s, 6H), 2.19 (s, 31), 2.4 (t, 2H), 3.05 (s, 3H), 3.5-3.54 (m, 4H) 3.65-3.72 (m, 6H), 6.75 (s, 1H), 6.94 (d, 1H), 7.02 (s, 1H), 7.1 (d, 1H), 7.24 (d, 2H), 7.58 (d, 1H), 7.78 (s, 1H), 8.19 (d, 1H), 8.26 (d, 1H), 9.96 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H+ 518.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]([CH:25](OC)OC)[CH:20](OC)OC)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH:31]C(=O)C1C=CC=CC=1)=[N:10]2.[CH3:40][NH:41][NH2:42].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([C:19]3[CH:25]=[N:42][N:41]([CH3:40])[CH:20]=3)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH2:31])=[N:10]2
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: CNN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](c3cnn(C)c3)C[C@@H]12
Temperature: 70 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C75) [prepared from P4 via a method similar to that used for the conversion of P1 to C44 in Preparation P3 and Example 5](297 mg, 0.526 mmol) was combined with ethanol (1.75 mL) and methyl hydrazine (36.4 mg, 0.789 mmol) followed by addition of water (0.6 mL). Concentrated sulfuric acid (55 μL, 1.0 mmol) was slowly added and the reaction mixture was heated at 70° C. for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted three times with ethyl acetate; the combined organic layers were extracted three times with 0.2 M aqueous hydrochloric acid, and the combined aqueous layers were washed with ethyl acetate. The pH was adjusted to 9-10 by addition of 1 M aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) provided the product as an off-white solid. Yield: 109 mg, 0.287 mmol, 55%. LCMS m/z 379.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.22-7.28 (m, 1H), 6.85-6.92 (m, 2H), 4.57 (dd, J=11.3, 2.3 Hz, 1H), 4.16 (dd, J=11.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J=11.3, 1H), 3.01-3.06 (m, 1H), 2.78 (dt, J=11.9, 3.8 Hz, 1H), 1.75-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:9])([F:25])[F:26])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1)[CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 100.5 %

Procedure:
N,N-diethylethylene diamine (2.50 kg, 21.12 moles) was added to a solution of 4-(4-trifluoromethylphenyl)benzaldehyde (3.54 kg, 14.08 moles) in toluene (21 L) and rinsed in with toluene (14 L) with stirring. The resultant solution was stirred at 17-21° C. for ca. 96 hours. The solution was then transferred to a hydrogenation vessel containing 5% palladium on alumina (0.213 kg, 0.11 moles Pd) and rinsed in with toluene (37 L). The mixture was hydrogenated at 19−27° C., 50 psig hydrogen for 1 hour until no further hydrogen was consumed. The catalyst was removed by filtration through celite (0.5 kg) and the celite bed was washed with toluene (14 L). The combined filtrate and wash were washed with process water (3×14 L) then the toluene removed by distillation at 20-80° C. in vacuo to give the title compound as a pale yellow oil (4.96 kg, 97.3%). 1H NMR (CDCl3) δ 1.01 (6H, t), 2.52 (4H, q), 2.58 (2H, t), 2.70 (2H, t),3.86 (2H, s), 7.42 (2H, d), 7.43 (2H, d), 7.68 (4H, s).