Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCNC1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(Cl)cc2)C1
Yield: 79 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 4-chloro-benzoyl chloride to afford the title compound as a pale yellow oil (3.02 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=2)[N:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(Cl)nc2ccc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nc(Cl)cc(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl (2-chloro-6-methylquinolin-4-yl)propanedioate (100 mg, 0.30 mmol) in methanol (2 mL) was added an aqueous solution of sodium hydroxide (2 N, 2 mL) and the resulting mixture was stirred at room temperature overnight. The reaction was then acidified to pH 4 with an aqueous solution of hydrochloric acid (5 N), and extracted with ethyl acetate (10 mL×3). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the desired product as a white solid. MS (ESI+) [(M+H)+] 236.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[C:5]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[NH4+]>C1COCC1>[C:5]([N:12]1[CH2:17][CH2:16][C:15]([OH:18])([C:1]#[CH:2])[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of ethynylmagnesium chloride in THF (100 mL, 50 mmol) was diluted with THF (50 mL) and cooled in an ice-water bath. A solution of Boc-4-piperidone (5.06 g, 25.4 mmol) (Aldrich) in THF (50 mL) was added dropwise over 15 min. The mixture was stirred with cooling for 3 h. Aqueous ammonium chloride solution (100 mL, 15% W/V) was then added and the resulting mixture extracted with ether (2×200 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 mL), then combined, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (Biotage 40M, ethyl acetate - hexanes 1:3, V/V as solvent) to give N-Boc-4-hydroxy-4-ethynyl-piperidine as a colorless oil that solidified on standing. (Yield 5.39 g, 94.2%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[OH-].[K+].[CH3:23]I>O1CCCC1>[CH:18]1([CH2:17][O:16][C:10]2[CH:9]=[C:8]([C:2]3([CH3:1])[O:6][C:5](=[O:7])[N:4]([CH3:23])[CH2:3]3)[CH:13]=[CH:12][C:11]=2[O:14][CH3:15])[CH2:20][CH2:19]1
Reactant: CI
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CN(C)C(=O)O2)cc1OCC1CC1
Yield: 40.4 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone, 113 mg (2.0 mmol) of potassium hydroxide, and 0.15 ml (2.2 mmol) of methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The reaction mixture was filtered, the filtrate combined with 30 ml of water and then extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate, filtered, and concentrated (390 mg of a yellow oil). By PSC separation with methylene chloride/ether (1:1), 212 mg of 5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone was obtained as an oil.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:40]([O:41]CC2C=CC=CC=2)[C@H:39]([O:49][C@@H:50]2[O:79][C@H:78]([CH3:80])[C@@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]([O:61]CC3C=CC=CC=3)[C@H:51]2[O:52]CC2C=CC=CC=2)[C@@H:38]([CH2:81][O:82]CC2C=CC=CC=2)[O:37][C@@H:10]1[O:11][C@@H:12]1[CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[C@H:14]([CH2:27][O:28]CC2C=CC=CC=2)[C@H:13]1[OH:36])C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:50]1([O:49][C@@H:39]2[C@@H:38]([CH2:81][OH:82])[O:37][C@H:10]([O:11][C@@H:12]3[CH2:16][NH:15][C@H:14]([CH2:27][OH:28])[C@H:13]3[OH:36])[C@H:9]([OH:8])[C@H:40]2[OH:41])[O:79][C@H:78]([CH3:80])[C@@H:69]([OH:70])[C@H:60]([OH:61])[C@H:51]1[OH:52]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3CN(C(=O)OCc4ccccc4)[C@H](COCc4ccccc4)[C@H]3O)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@@H]3CN[C@H](CO)[C@H]3O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The compound (90 mg, 74.6 μmol) synthesized in Example 12 (12a) was dissolved in methanol (10 mL) and hydrochloric acid (140 μL) and 20% palladium hydroxide-carbon (90 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 2 hours. After the celite filtration, ammonia water (5%) was added thereto until the pH became neutral. The solvent was distilled off under reduced pressure and the residue was purified by ion exchange resin (Dowex 50w×8) column (water-5% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (26 mg, 79%) as a colorless solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:26]([O:28]C)=[O:27])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:26]([OH:28])=[O:27])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cccc(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2cccc(O)c2)C(=O)O)cc1
Reaction time: 17 h
Yield: 52.6 %

Procedure:
To methanol (240 mL) solution of the compound obtained in Example 36 (3.1 g) was added dropwise 1 mol/L of an aqueous sodium hydroxide solution (24 mL) at room temperature, and the mixture was allowed to stir for 17 hours. To the residue obtained by distilling off the solvent under a reduced pressure was added water, and the mixture was made acidic with dilute hydrochloric acid, and thereafter extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, to give the captioned compound (1.4 g, 51%) as an amorphous solid product.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.[Cl:26][C:27](S(Cl)(=O)=O)=[CH2:28]>ClCCl>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:28]=[C:27]([Cl:26])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: C=C(Cl)S(=O)(=O)Cl
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(Cl)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (Reference Example 2) (1.0 g, 2.7 mmol) and 1-chloro-1-ethenesulfonyl chloride (Intermediate 4) (1.1 g, 6.8 mmol) were heated to 90° C. for one hour with stirring. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and applied onto a silica gel column. Elution with hexanes/acetone (1.5:1) gave 0.745 g (64%) of the title compound as a colourless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])[CH:11]=1>FC(F)(F)C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])[CH:11]=1
Reactant: Cc1cccc(C(=O)Nc2cc(-c3cc4ccccc4o3)ccc2C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2cc(-c3cc4ccccc4o3)ccc2C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(benzofuran-2-yl)-2-(2,3-dimethylbenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and ethyl acetate was added to the obtained residue and a solid substance was separated by filtration to obtain 15 mg of 4-(benzofuran-2-yl)-2-(2,3-dimethylbenzamido)benzoic acid as white solid.
Reaction SMILES: C(Cl)(Cl)Cl.[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.Br[CH2:17][CH2:18][CH2:19][OH:20]>C(N(CC)CC)C>[OH:20][CH2:19][CH2:18][CH2:17][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: OCCCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SCCCO)cc1
Yield: 67 %

Procedure:
To 40 ml of chloroform were added 4.0 g of methyl 4-mercaptobenzoate, 3.3 g of 3-bromo-1-propanol and 2.38 g of triethylamine, and the mixture was stirred for an hour and then evaporated under a reduced pressure. After adding 50 ml of ethyl acetate, the mixture was washed with 30 ml each of water, 1N hydrochloric acid and a saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/methanol (100:3) to obtain 3.6 g of methyl p-(3-hydroxypropylthio)benzoate as a colorless crystal. To 3.0 g of this crystal was added 1.44 g of phosphorus tribromide, and the mixture was heated at 80° C. for 2 hours, poured into 50 ml of ice-water, and extracted three times with 20 ml of ethyl acetate. The extract was dried over magnesium sulfate, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/hexane (1:1) to obtain 3.0 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:61][S:62]([CH2:65][CH2:66][NH2:67])(=[O:64])=[O:63]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O.C(N(CC)CC)C>[CH3:61][S:62]([CH2:65][CH2:66][NH:67][C:34](=[O:36])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:32][CH2:31]1)(=[O:64])=[O:63]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 2-(methylsulfonyl)ethaneamine hydrochloride (90 mg), and triethylamine (120 μL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) to give the title compound (111 mg, yield 62%) as a pale-yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([C:15]#[C:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)[S:13][CH:14]=2)[C:5]([C:26]#[N:27])=[C:4]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][OH:18])[S:13][CH:14]=2)[C:5]([C:26]#[N:27])=[C:4]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#Cc1nc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(CCCO)n1

Procedure:
Under argon, 220 mg of the mixture from Example 22A were initially charged in 10 ml of ethyl acetate, 110 mg of palladium (10% on activated carbon) were added and the mixture was hydrogenated at atmospheric hydrogen pressure and room temperature overnight. The catalyst was filtered off through Celite, the filter cake was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by preparative HPLC. This gave 31 mg (17% of theory) of the target compound.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[N:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH3:23])[C:13](=[O:24])[C:12]=2[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:8]=[CH:9][CH:10]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(N(CC)CC)C>C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[N:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH3:23])[C:13](=[O:24])[C:12]=2[CH:25]2[CH2:30][CH2:29][N:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:27][CH2:26]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: CCn1c(=O)c(C2CCNCC2)c(-c2cccc(Br)c2)c2ccc(C)nc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(c2c(-c3cccc(Br)c3)c3ccc(C)nc3n(CC)c2=O)CC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a 5 ml acetonitrile solution containing 400 mg of 4-(3-bromophenyl)-1-ethyl-7-methyl-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one were added 0.11 ml of ethyl bromoacetate and 0.13 ml of triethylamine, followed by stirring at room temperature for 13 hours. Ethyl acetate was added to the reaction solution and the solution was washed with saturated sodium bicarbonate aqueous solution and saturated brine and dried over anhydrous magnesium sulfate. After removal of the solvent from the organic layer, the resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 120 mg of ethyl {4-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-l,8-naphthyridin-3-yl]piperidin-1-yl}acetate as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:24]=[C:25]([NH:26][C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=3[N+:13]([O-:15])=[O:14])[CH:27]=[CH:28][CH:29]=2)[CH2:18]1
Reactant: CN1CCCC(c2cccc(N)c2)C1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(Nc2cccc(C3CCCN(C)C3)c2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 1c (5.7 g, 25 mmol), 2j (3.8 g, 20 mmol) and potassium carbonate (3.45 g, 25 mmol) was heated to 70° C. under a stream of nitrogen. The resulting melt was stirred at 70° C. overnight. The reaction mixture was partitioned between water and ethyl acetate and the organic phase was extracted with diluted hydrochloric acid (4M). The aqueous phase was rendered alkaline by addition of aqueous sodium hydroxide (4M) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to leave ethyl 4-(3-(1-methylpiperidin-3-yl)phenylamino)-3-nitrobenzoate (7.5 g, 98%) as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(F)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (25 mg, 0.074 mmol) (from Example 5 supra) and Et3N (21 μL , 0.148 mmol) in 3 mL of chloroform was treated with 4-fluorobenzoyl chloride (10.5 μL , 0.088 mmol) (Aldrich). The resulting reaction mixture was stirred at room temperature for 8 h and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-fluorobenzamide (yield: 26 mg, 83%) as a yellow solid (mp 130-131° C.).
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33]C(=O)C)[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][O:21]C(=O)C)=[O:16])=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:6][CH:5]([CH2:4][OH:3])[C:7]([NH:9][C:10]1[C:11]([I:37])=[C:12]([CH2:32][OH:33])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH2:18][CH:19]([OH:25])[CH2:20][OH:21])=[O:16])=[O:8]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(NC(=O)C(O)CO)c1I
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carbamido)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (0.80 g, 9.16 mmol) was dissolved in methanol (7 ml) and potassium carbonate (0.17 g, 12,3 mmol) was added. The mixture was stirred at room temperature for 17 h. The mixture was filtered and pH of the filtrate was adjusted to 1 using aqueous 5M hydrochloric acid, and the mixture was stirred for further 5 h at room temperature. The reaction mixture was then evaporated to a solid residue, which was purified by preparative HPLC. Yield: 0.41 g (49%) of a white freeze dried product.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+]>C1COCC1.O.C(O)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:4]([C:3]([OH:33])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:22]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)OC)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)O)CCCC1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (69 mg, 0. 145 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (24.3 mg, 0.58 mmol) in water (1.0 mL). Sufficient THF was added to the mixture to effect solution. The mixture was stirred 1 hr and a few drops of acetic acid were added. The entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a linear gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl] -L-phenylalanine (48 mg, 72%) as a white solid. LR-Electrospray: m/z positive ion 943 (2M+Na), 483 (M+Na), 478, (M+NH4), 461 (M+H); negative ion 919 (2M−H), 521, 459 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:20])=[O:21])=[O:24])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc(OC)n1

Procedure:
To 15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 300 ml of dry methylene chloride containing 0.1 g 1,4-diazabicyclo[2,2,2]octane was added 21 g 2-chlorobenzenesulfonyl isocyanate with stirring. The mixture was stirred for 16 hours and the resultant solid was removed by filtration. After washing the solid with 1-chlorobutane, the resulting product, N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)-aminocarbonyl]-2-chlorobenzenesulfonamide melted at 188°-189° C. Infrared absorption analysis showed absorption peaks at 1740 cm-1, 1630 cm-1 and 1595 cm-1 which are typical for this type of compound.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:25][C:24]=1[CH2:36][C:37](O)=[O:38].P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[CH:25][C:24]=1[CH2:36][C:37]([NH:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1)=[O:38]
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: O=C(O)Cc1cc(-c2ccc(Cl)cc2)ccc1Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2Cl)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). 3.07 ml of triethylamine were added dropwise at 20° C., the mixture was stirred for 5 min, and 2.81 g (10 mmol) of (4,4′-dichlorobiphenyl-3-yl)acetic acid (EP 1943218 A1 and US 2009/215624 A1) were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 3.3 g (59% of theory) of the title compound of melting point 146-147° C.