Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:20]([F:22])([F:21])[F:23])[CH:18]=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C1CC(c2cccc(Br)c2)=Nc2ccc(C(F)(F)F)cc2N1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)c1

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.2) (200 mg, 0.50 mmol) and commercially available 3-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 221290-14-8] (161 mg, 0.60 mmol) according to the general procedure II. Obtained as an off-white solid (31 mg, 12%). MS (ISP) 515.9 [(M+H)+]; mp 179-181° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:21]([O-])([N+]([O-])=O)=[O:22]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 70.8 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.4 g of 1-(2-chloroethyl)-1-nitroso3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:8][C:12]([CH:9]1[CH2:11][CH2:10]1)=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)C1CC1
Reactant: CCCCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCC(C)OC(=O)C1CC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
2-Heptanol (200 g, 1.72 mol) and cyclopropanecarboxylic acid (163 g, 1.90 mol) were added into toluene (500 mL), followed by p-toluenesulfonic acid (3.2 g, 0.0172 mol). The reaction mixture was heated to reflux for 6 hours, cooled to room temperature, and quenched with aqueous sodium bicarbonate (1 L). The reaction mixture was then washed with brine (0.5 L) and dried over sodium sulfate (50 g). The solvent was removed and the reaction mixture was distilled to provide the product cyclopropanecarboxylic acid 1-methyl-hexyl ester (253 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2].[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:27][CH2:26][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc(S(C)=O)ccc3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(S(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 11.1 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-(methylsulfinyl)-1H-pyrazolo[3,4-b]quinoline (0.4 g, 2.8 mmol), DMSO (1.5 mL) and cyclohexylmethylamine (0.73 mL, 5.6 mmol) was heated at 110° C. over night. The reaction mixture was cooled to room temperature, then was partitioned between CHCl3 (20 mL) and water (20 mL) containing NH4OH (3 mL). The layers were separated, the aqueous layer was extracted with CH2Cl2 (10 mL) and the organic layers were combined dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate, followed by recrystallization from ethyl acetate (2×) to afford 0.115 g of 1-ethyl-6-(methylsulfinyl)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 186°-187° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[NH:29])[NH:24][O:25][C:26](=O)C)=[CH:13][CH:12]=2)[C:8]2[C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=S)=[S:39].[H-].[Na+]>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][O:25][C:26](=[S:39])[N:29]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NOC(C)=O)cc1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=S)o[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a mixture of methyl 2-butyl-1-[[2'-(acetoxycarbamimidoyl)biphenyl-4-yl)methyl]benzimidazole-7-carboxylate (2.0 g) and CS2 (1.5 g) in DMF (12 ml) was added sodium hydride (60% in oil, 0.56 g) during a period of 10 minutes and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water and the pH of the solution was adjusted to 3. The mixture was extracted with ethylacetate and the extract was washed with water, dried, and concentrated to dryness. The residue was crystallized from chloroform-methanol to afford pale yellow prisms (0.64 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[C:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:14])(=[O:13])=[O:12])#[N:5]
Reactant: Cc1cccc(N)c1C#N
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: Cc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-methylbenzonitrile (1.32 g, 10 mmol) and sulfamide (4.81 g, 50 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7) to give the title compound as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.19-7.21 (m, 3H), 7.39-7.41 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 9.41 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=[C:2]2[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(Cl)c2ccc(C)c(F)c2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C)c(F)c2n1
Temperature: 75 °C
Yield: 80.9 %

Procedure:
Methyl 4-chloro-8-fluoro-7-methylquinoline-2-carboxylate (7-8, 993 mg, 3.91 mmol), (4-Fluorophenyl)boronic acid (575 mg, 4.11 mmol), and Pd(Ph3P)4 (226 mg, 0.196 mmol) were dissolved in degassed toluene (25 mL). Degasses EtOH (2.7 mL) was added followed by degassed 2M aq. Sodium Carbonate (4.31 mL, 8.61 mmol). The reaction was heated at 75° C. overnight then quenched with water and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was triturated with ether to afford Methyl 8-fluoro-4-(4-fluorophenyl)-7-methylquinoline-2-carboxylate (7-9, 991 mg, 81% yield) as a tan solid, LCMS shows the compound is 89% pure, LRMS m/z (M+H)+ 314.1 found, 314.0 required.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN2C(=O)CC(CC(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.500 g, 1.35 mmol), methyl 4-(bromomethyl)benzoate (0.370 g, 1.62 mmol), and potassium carbonate (0.56 g, 4.05 mmol) in DMF (6 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 20:80) to provide methyl 4-[(4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)methyl]benzoate (0.604 g, 86%) as a white amorphous.
Reaction SMILES: [O:1]=[C:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:5](=[O:6])[CH:4]=[C:3]1[CH3:11]>C(Cl)Cl>[CH3:10][C:8]1([CH3:9])[CH2:7][C:5](=[O:6])[CH2:4][C@@H:3]([CH3:11])[C:2]1=[O:1]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Solvent: ClCCl
Product: C[C@@H]1CC(=O)CC(C)(C)C1=O

Procedure:
The water phase (190 liters+ 5 liters of wash-water) is stirred out five times with 60 liters of methylene chloride each time. The solvent phase is separated, washed twice with 60 liters of water each time and concentrated to about 15 liters on a rotary evaporator. This concentrate is dehydrated with 1.5 kg of sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue (1755 g) is dissolved while hot in 6 liters of diisopropyl ether, decolourised with 80 g of active carbon, filtered over diatomaceous earth padding and rinsed with 1.8 liters of hot diisopropyl ether. From this solution, 2.6 liters of diisopropyl ether are distilled off at normal pressure, such that the product remains dissolved in a three-fold amount of diisopropyl ether. The product is crystallised overnight at 5° C., filtered off under suction, washed twice with 1500 ml of cold n-hexane each time and dried for 15 hours at 40° C. under reduced pressure. This first crystallisation produces 1280 g of optically pure [6R]-2,2,6-trimethyl-1,4-cyclohexanedione of melting point 91°-92° C. The mother liquor contains a further 447 g of substances. The latter is taken up in the same amount of n-hexane, treated with diisopropyl ether until the solution is clear, crystallised overnight at 5° C., filtered off under suction and washed twice with a small amount of cold n-hexane. The crystallisate is dried at 40° C. under reduced pressure. This second crystallisation produces 83.6 g of produce with a melting point of 70°-88° C. After triple recrystallisation with the three-fold amount of diisopropyl ether, there are obtained a further 43 g of optically pure [6R]-2,2,6 -trimethyl-1,4-cyclohexanedione of melting point 90.5°-91.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH:18]=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc3ccccc3s2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2sc3ccccc3c2C=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-methylphenyl)benzo[b]thiophene (896 mg) in freshly distillated tetrahydrofuran (15 ml) was added n-butyllithium (2.75 ml, 1.6 mol solution in n-hexane) through a syringe at -78° C. The solution was stirred at -78° C. for 10 minutes and then at ambient temperature for half an hour. To the deep red colored solution was added N,N-dimethylformamide (365 mg) at 5° C. The mixture was stirred at ambient temperature for one hour, quenched with aqueous saturated ammonium chloride solution, and extracted with diethyl ether. The organic layer was washed with aqueous saturated ammonium chloride solution, dried, and concentrated in vacuo to give a yellow residue, which was purified by flash column chromatography on silica gel eluted with 50% n-hexane in dichloromethane to yield 2-(4-methylphenyl)benzo[b]-thiophene-3-carbaldehyde (285 mg) as white crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][NH2:10])=[CH:5][CH:6]=1.C(O[CH:14]=[C:15]([C:21]([CH3:23])=O)[C:16]([O:18]CC)=[O:17])C>>[CH3:23][C:21]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:9]([CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:10]=1
Reactant: NNCCc1ccccc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Product: Cc1nn(CCc2ccccc2)cc1C(=O)O
Yield: 37.1 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using phenelzine (15 g) and ethyl 2-ethoxymethyleneacetoacetate (12 g), the residue was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give 3-methyl-1-phenethylpyrazole-4-carboxylic acid (5.5 g).
Reaction SMILES: I.[CH3:2][N:3]([C:12]([S:14][CH3:15])=[NH:13])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16]([O:19][CH2:20][C:21](Cl)=[O:22])(=[O:18])[CH3:17]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[C:16]([O:19][CH2:20][C:21]([N:13]=[C:12]([N:3]([CH3:2])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[S:14][CH3:15])=[O:22])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(=NC(=O)COC(C)=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Methyl 1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate, hydroiodide (1.34 g) was dissolved in saturated potassium carbonate solution and extracted with ether. The combined organic extracts were dried and evaporated to give an off-white solid which was dissolved in acetone (25 ml) and treated with potassium carbonate (1.1 g) followed by (acetyloxy)acetyl chloride (0.85 g). The suspension was stirred at room temperature for 2 h and evaporated in vacuo. The residue was suspended in water (50 ml) and filtered to give the title compound (1.01 g) which was recrystallised from ethanol, m.p. 115°-117°.
Reaction SMILES: [CH:1](/[C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:25].CCOCC.[H][H]>CO.[Pd]>[ClH:25].[CH2:1]([C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCC(O)CNc1cc(/C=C/c2ccccc2)nc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OCC(O)CNc1cc(CCc2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 29 %

Procedure:
(E)-(RS)-3-(2-Styryl-quinolin-4-ylamino)-propane-1,2-diol (0.23 g, 0.718 mmol) was dissolved in MeOH (25 ml) and acidified with HCl/Et2O. The reaction mixture was refluxed for 2 hours in the presence of 10% Pd/C (0.02 g) under an atmospheric pressure of hydrogen. The mixture was cooled to room temperature, the catalyst was filtered, and the filtrate was concentrated. Addition of EtOH provided (RS)-3-(2-phenethyl-quinolin-4-ylamino)-propane-1,2-diol hydrochloride (0.075 g, 29%) as a light yellow solid, m. p. 143-145° C., MS: m/e=323.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([O:30]C)=O)=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH2:33]>>[CH2:1]([O:8][C:9]1[C:10]([C:28]([NH:33][CH3:32])=[O:30])=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(C)C2
Product: CNC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)C(C)C2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-5-(4-fluorobenzyl)-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to that described in Example 5, Step 3, except that methylamine (2M in MeOH) was used in place of 4-fluorobenzylamine, and the reaction was heated to reflux overnight. The solvent was removed in vacuo, and the material was used without purification. ES MS (M+1)=423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:34][CH2:35]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1

Procedure:
Prepared from 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (20 mg, 0.0408 mmol, prepared according to Example 7, Step B) and 1-(2-methoxyethyl)-piperazine (17.6 mg, 0.122 mmol) according to the procedure described for Example 138, Step C. Yield: 12 mg (51%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2Cl)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)piperidine-4-carboxylate hydrochloride (2.8 g, 8.63 mmol) was diluted with DCM (24.18 mL). DIPEA (3.76 mL, 21.56 mmol) and methyl carbonochloridate (0.815 mL, 10.35 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, then washed with 3×0.1 M HCl and brine. Filtered through a phase separator. Evaporated to yield dimethyl 2-(2,4-dichlorophenyl)piperidine-1,4-dicarboxylate (2.78 g, 93%) as an oil. MS m/z 346 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture containing 2,4-dinitrophenylacetic acid (100 g, 0.442 mol), concentrated sulfuric acid (1.5 mL) and ethanol (700 mL) is heated at reflux for 61/2 hours, cooled to room temperature and filtered. The filtrate is concentrated in vacuo to a volume of 200 mL then diluted with water. The pH of the aqueous mixture is adjusted to about a with solid sodium hydrogen carbonate and extracted with ether. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, decolorized with charcoal and concentrated in vacuo to obtain the title compound as a yellow oil (102.4 g).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1([F:37])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:28]=2[O:27]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:37][C:26]1([F:25])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:17]([C:12]4[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:7]5[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:24])[F:1])=[CH:5][CH:6]=5)[N:11]=4)=[CH:18][CH:19]=[N:20]3)[C:28]=2[O:27]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=461.3 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([OH:36])=[O:35].C(N(CC)CC)C.C([O-])(=O)C.[Na+:48]>CC(C)=O>[CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([O-:36])=[O:35].[Na+:48]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1

Procedure:
The ceftriaxone acid was dissolved in aqueous acetone using triethylamine. To the clear solution obtained, sodium acetate (13 g) was added and charcoalized. To the filtrate, acetone (720 mL) was added over 1-2 h and filtered to get ceftriaxone sodium. The wet material of ceftriaxone sodium thus obtained was dissolved in water (120 mL) followed by addition of acetone (222 mL). The solution was cooled to −5 to −15° C. and the impurity separated as a sticky mass. The clear solution was separated and the temp raised to 18-22 C. Acetone (624 mL) was added under stirring over 1 h, filtered and washed with acetone. Drying under vacuum afforded pure ceftriaxone sodium.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1.[N:31]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:15]=[C:16]3[C:22]4[CH:23]=[C:24]([C:27]([N:34]5[CH2:35][CH2:36][N:31]([CH2:37][CH2:38][OH:39])[CH2:32][CH2:33]5)=[O:28])[CH:25]=[CH:26][C:21]=4[O:20][CH2:19][CH2:18][N:17]3[CH:30]=2)=[N:12][CH:11]=[N:10]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2
Product: O=C(c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2)N1CCN(CCO)CC1

Procedure:
Following the procedure for 109, 2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(piperazin-1-yl)ethanol gave 162. MS: (ESI+)=522.2