Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:29][C:28](=[O:30])[C:27]2=[C:31]([CH3:39])[N:32]=[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:26]2[N:25]=1)[CH3:2].[OH-].[Na+].O>CO.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:29][C:28](=[O:30])[C:27]2=[C:31]([CH3:39])[N:32]=[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:26]2[N:25]=1)[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(OCC)c(-c3nn4c(C5CCCC5)nc(C)c4c(=O)[nH]3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N2CCC(C(=O)O)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
180 mg (0.323 mmol) of the ester from Example 8 and 50 mg (1.29 mmol) of sodium hydroxide are stirred at room temperature in 20 ml of methanol/water 3:1 for minutes, 10 ml of water are added and the mixture is extracted once with dichloromethane. The aqueous phase is acidified using 2 n HCl and extracted twice with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and evaporated. The residue is recrystallized from diethyl ether.
Reaction SMILES: [H][H].[CH3:3][C:4]1([CH3:20])[C@@H:6]([C:7]#[C:8][C:9](=[O:16])[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C@H:5]1[C:17]([OH:19])=[O:18].N1C2C(=CC=CC=2)C=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:3][C:4]1([CH3:20])[C@@H:6](/[CH:7]=[CH:8]\[C:9](=[O:16])[O:10][CH2:11][C:12]([F:15])([F:13])[F:14])[C@H:5]1[C:17]([OH:19])=[O:18]
Reactant: [H][H]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Yield: 64.5 %

Procedure:
500 mg of 10% palladium hydroxide on barium sulfate and 5 ml of ethyl acetate were placed in a round flask connected to a hydrogen apparatus and 2 g of the product of Step C, 45 ml of ethyl acetate and 0.5 ml of quinoline were added thereto. Hydrogenation was carried out until hydrogen absorption ceased and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water and evaporated to dryness. The 2 g of residue were chromatographed over silica gel and eluted with a 70-20-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 1.3 g of (1R,cis) 2,2-dimethyl-3-[(Z )-3-oxo-3-(2,2,2-trifluoro-ethoxy)-1-propenyl]cyclopropane-carboxylic acid.
Reaction SMILES: [CH2:1]([N:4]([C:19]([O:21][CH2:22][C:23]1C=CC=CC=1)=[O:20])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([F:18])[CH:6]=1)C=C.N1C=CC=CC=1.[I:35]I>C(Cl)(Cl)Cl>[I:35][CH2:23][CH:22]1[O:21][C:19](=[O:20])[N:4]([C:5]2[CH:6]=[C:7]([F:18])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[C:9]([F:11])[CH:10]=2)[CH2:1]1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2cccnc2)c(F)c1
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Reaction time: 1.5 h

Procedure:
N-Allyl-N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION 4, 496 mg 1.31 mmol) in chloroform (25 ml), pyridine (1.58 ml, 19.6 mmol, 15 eq) and iodine (4.97 g, 19.6 mmol, 15 eq) are combined. The resulting mixture is placed under an atmosphere of nitrogen and heated to 50° with stirring. After 1.5 hr, the reaction is decanted into chloroform (70 ml). The remaining sludge is rinsed with chloroform (3×15 ml). The combined organics are washed with sodium thiosulfate (20%), then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give a solid. This material is purified by silica gel chromatography (100 g) eluting with methanol/chloroform (0.5/99.5-1 l, 1/99, 1 l). The appropriate fractions are pooled and concentrated to give the title compound, mp 133-134°; FTIR (mull) cm-1 3130, 1758, 1650, 1414, 1241, 1017 and 846; NMR (CDCl3) 8.72, 8.62, 7.79, 7.43-7.38, 7.32, 4.84-4.72, 4.19, 3.80, 3.51 and 3.39 δ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:32]#[N:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2([C:32]#[N:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:43])[CH3:28])[O:22][C:21]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)[CH:2]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)CC3)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)CC3)c(F)c2)C(=O)O1
Yield: 58 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)—N-{3-[4-(4-(pyridin-3-ylamino)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 58% yield.
Reaction SMILES: [CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(CCCCCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
2-isopropyl-7-phenylheptanoic acid (1.0 g; prepared as the intermediate for the compound of example 1 (b)) was dissolved in anhydrous acetic acid (5ml). The solution was cooled in an ice-bath. Fuming nitric acid (0.4 ml) was dropped into the solution. The solution was stirred for 30 mins. Anhydrous acetic acid was quenched by adding potassium hydroxide to the reaction solution. The reaction solution adjusted to pH 6.0~7.0 was extracted with ethyl acetate. The ethyl acetate layer separated was washed with water, followed by saturated brine, dried and then evaporated. The residue was purified by column chromatography on silica gel to give the title compound (850 mg) having the following physical data:
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.B(F)(F)F.CCOCC>[CH2:21]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)O1
Reaction time: 48 h
Yield: 5 %

Procedure:
In 5 ml of dichloromethane were dissolved 155 mg of Compound (1) and 119 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added two drops of boron trifluoride etherate (47% ether solution) and 2 g of Molecular Sieves (3A). The mixture was allowed to stand at room temperature for 2 days. The reaction solution, after removing the Molecular Sieves, was washed with a cooled aqueous solution of sodium hydrogen carbonate, followed by drying (MgSO4). The solvent was evaporated off under reduced pressure, and the residue was purified by subjecting to a silica gel preparative thin-layer chromatography [developed with 1,2-dichloroethane-ethyl acetate (5:1)] to give 12.5 mg of the subject Compound (9).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH:14](=[N+:21]([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:22][N:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[N:1]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=1)[CH3:23]
Reactant: Nc1ccccc1-n1cccc1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1cccn1-c1ccccc1N

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 9.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[N:3]1.[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(I)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cn1cc(C#Cc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-4-iodopyrazole (208 g, 1 mol) and phenylacetylene (112 g, 1.1 mol) in diisopropylamine (2 l) are added, under nitrogen, copperiodide (2 g), triphenylphosphine (0.1 g) and bis-(triphenylphosphine) palladiumdichloride (0.5 g). The mixture is kept during 3 hours at ca. +35° C. and then heated for 1 hour at +90° C. The cooled reaction mixture is diluted with ethyl acetate and filtrated. Concentration of the filtrate and distillation yields the title compound: b.p. 116°-118° C./0.3 mbar, m.p. 70°-72° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc(CN2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Yield: 79.2 %

Procedure:
4-carboxyphthalic anhydride (0.5 g, 0.0026 mol) and 4-(aminomethyl)benzoic acid (0.39 g, 0.0026 mol) were refluxed as above overnight. Crystallisation of the product from 1,4-dioxane/H2O yielded 0.67 g (79%) of 108 as a white solid: mp=365-366° C.; Rf0.76 (A): Rf0.71 (C): Rf0.50 (D): IR (cm−1): 2800-3100 (OH), 3071 (C═CH), 2678 (C—H), 1782 (C═O), 1712 (bs, C═O), 1611 (C═C), 1577 (C═C), 1428 (C═C), 1391 (C—O), 1300 (C—O), 1105 (C—O), 734 (C═CH); MS m/z (rel intensity) 325 (20), 324 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 76 %

Procedure:
Prepared from 4-nitrophenylenediamine and 2-methoxybenzoic acid, in a manner similar to that of Example 9b. Yield: 76%; Rf (6/4 toluene/ethyl acetate): 0.43; IR (KBr): 3005, 1515, 1335, 750 cm−1.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31])#[N:9].CO>CC(C)=O>[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:27])=[O:7])=[CH:22][CH:21]=1)[C:14]([CH3:28])=[C:13]2[CH2:29][C:30]([OH:32])=[O:31])#[N:9]
Reactant: CSc1ccc(C=C2C(C)=C(CC(=O)O)c3cc(C#N)ccc32)cc1
Reactant: O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate (0.214 g.) (0.001 mole) in 3 ml. of water is added dropwise to 5-cyano-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid (0.001 mole) in 25 ml. methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° to give 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid, m.p. 160°-155° in from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:6][C:5]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)=[CH:4][C:3]=1[OH:57].[Br:58]Br.[Cl-].[NH4+]>CC(O)=O>[Br:58][C:4]1[C:5]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:19]2)=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[C:3]=1[OH:57]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(O)c2Cl)cc1
Reactant: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(O)c2Cl)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of compound 77 (2.36 g, 3.0 mmol) in AcOH (30 mL) were added TEA (0.6 mL, 4.51 mmol) and Br2 (0.18 mL, 3.61 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and at room temperature for 15 hours. To a mixture was added saturated ammonium chloride and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was carried on to the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH2:38])[CH:33]=[CH:34][C:35]=1[Cl:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH:38][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: NCc1ccc(Cl)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(Br)c1

Procedure:
A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (600 mg, 1.541 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (397 mg, 1.8 mmol), HATU (760 mg, 2.0 mmol), and triethylamine (0.488 ml, 3.5 mmol) in 25 mL of DCM was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide. LC-MS m/z 591.2 (M+H)+, 0.84 min (ret time).
Reaction SMILES: [CH2:1]=C1CCN(C2C([N+]([O-])=O)=CC=CN=2)CC1.[C:17]([N:24]1[CH2:28][CH2:27][C:26](=O)[CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[CH2:1]=[C:26]1[CH2:27][CH2:28][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Product: C=C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was synthesised following the method described here for Compound 2a using 1-Boc-3-pyrrolidinone instead of 1-(3-nitro-2-pyridyl)-4-oxopiperidine. After the usual work-up procedure, the crude product was purified by automated flash chromatography (Horizon®TM-Biotage) eluting with a Petroleum Ether-EtOAc gradient from 95:5 to 7:3, yielding the title compound as brownish oil. Yield: 75.8%.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([C:7]1[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:20]=1)[CH2:4][CH2:5][CH3:6].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[NH2:2][C:11]1[C:10]2[N:20]=[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:9]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)Nc1ccccc1

Procedure:
Concentrated ammonium hydroxide (35 mL) was added with stirring to a solution of N-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea (2.25 g, 5.39 mmol) in dichloromethane (100 mL). Tosyl chloride (1.13 g, 5.93 mmol) was added in small portions over a period of 30 minutes. After 1 hour the layers were separated. The aqueous layer was extracted with dichloromethane (2×25 mL). The organics were combined and extracted with water (3×50 mL). The aqueous layers were combined and filtered to provide 1.64 g of an off white solid. This material was recrystallized sequentially from 1,2-dichloroethane, isopropyl alcohol and methanol to provide 960 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea as light tan needles, m.p. 191-192° C. Analysis: Calculated for C24H28N6O: % C, 69.21; % H, 6.78; % N, 20.18. Found: % C, 68.94; % H, 6.77; % N, 19.90.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=1)=O)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].Cl.[NH2:38][OH:39].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[CH2:19]/[C:20](=[N:38]\[OH:39])/[C:22]1[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)cc1F

Procedure:
In analogy to example 151, step 3, 3-{3-fluoro-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=501.2.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38]CC4C=CC=CC=4)=[CH:34][CH:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(O)cc2)cc1
Yield: 97.9 %

Procedure:
A mixture of 4-tert-butyl-N-{6-[2-(4-benzyloxyphenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzensulfonamide (3.95 g), 10% palladium-carbon (1.5 g) and ethanol-tetrahydrofuran (80 ml-80 ml) is subjected to catalytic hydrogenation at room temperature under hydrogen atmosphere (1 atm) for 24 hours. The catalyst is removed by filtration, and the filtrate is concentrated. The residue is crystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-{6-[2-(4-hydroxyphenoxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (3.31 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Cc3ccncc3)c21
Yield: 27 %

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(pyridin-4-yl)acetic acid in 27% yield. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.21-1.37 (m, 1H), 1.48-1.70 (m, 4H), 1.71-1.82 (m, 1H), 3.01 (m, 1H), 3.78 (br s, 3H), 4.22 (br s, 1H), 4.43 (t, J=8 Hz, 1H), 5.05 (br s, 1H), 6.64 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 7.21 (d, J=8 Hz, 2H), 7.42 (t, J=8 Hz, 1H), 7.82 (br s, 2H), 8.43 (d, J=8 Hz, 2H), 10.67 (s, 1H). M+H=430.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>CO>[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COCCN
Solvent: CO
Product: COCCNCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl acrylate (4.4 ml) is dissolved in methanol (5 ml), and thereto is added 2-methoxyethylamine (3.1 ml). The mixture is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by distillation under reduced pressure to give tert-butyl 3-(2-methoxyethylamino)-propionate (4.61 g). Boiling point 98.0-102.0° C. (5.8 mmHg), MS (m/z): 204 [M+H]+.