Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:22][CH2:23][N:24]([CH2:32][CH2:33]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-benzyl amine (2.3 g, 8.8 mmol). Yield 3.33 g (99%); yellow oil; MS: 455.9 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH2:7][CH2:8]O.[Cr](O)(O)(=O)=O.S(=O)(=O)(O)[OH:19].[CH:23]([OH:26])(C)C>O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH2:7][CH2:8][C:23]([OH:26])=[O:19]
Reactant: O=S(=O)(O)O
Reactant: CC(C)O
Reactant: OCCCOc1cccc(F)c1
Agent: O=[Cr](=O)(O)O
Solvent: O
Product: O=C(O)CCCOc1cccc(F)c1

Procedure:
To a stirred solution of 12.0 grams (0.071 mole) of 3-(3-fluorophenoxy)propanol in 150 mL of acetone Jones reagent (a mixture of chromic acid and sulfuric acid in water) was added dropwise until an orange color persisted in the reaction mixture. Isopropanol was then added dropwise until the color of the reaction mixture became blue/green. The reaction mixture was then slurried with silica gel and filtered. The filter cake was washed with ethyl acetate. The combined wash and filtrate were concentrated under reduced pressure to a residue, which was dissolved in methylene chloride and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 12.8 grams of 3-(3-fluorophenoxy)propanecarboxylic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28]>CN(C=O)C>[ClH:25].[ClH:25].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc(-c3ccc(O)cc3)nn2)CC1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(-c3ccc(OCC(=O)N(C)C)cc3)nn2)CC1
Product: Cl
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 4-[6-(4-isopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenol (110 mg, 0.37 mmol) and 60% sodium hydride (58 mg, 1.45 mmol) in dry DMF (5 mL) was heated at 60° C. for 30 min. 2-Chloro-N,N-dimethylacetamide (54 mg, 0.44 mmol) was added and heating at 60° C. was continued for another 20 h. The reaction mixture was evaporated to dryness and partitioned between water (10 mL) and DCM (10 mL). The organic phase was isolated, washed with brine (5 mL), dried over anhydrous magnesium sulphate, and evaporated to dryness in vacuo. The residue was dissolved in hot ethyl acetate and HClg in Et2O was added to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:12][NH2:13])[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)(=[O:3])C.[CH:14](N)=[O:15].N.C[OH:19]>O1CCCC1>[C:14]([OH:15])(=[O:19])[C:1]([OH:4])=[O:3].[CH3:11][N:8]1[CH2:7][CH2:6][C:5]([CH2:12][NH:13][CH3:14])([OH:4])[CH2:10][CH2:9]1
Reactant: CO
Reactant: NC=O
Reactant: CC(=O)OC1(CN)CCN(C)CC1
Agent: N
Solvent: C1CCOC1
Product: CNCC1(O)CCN(C)CC1
Product: O=C(O)C(=O)O
Reaction time: 5.5 h

Procedure:
A mixture of 46 g (0.23 mole) of 4-(aminomethyl)-1-methyl-4-piperidinol acetate [1:1] and 10.2 g (0.23 mole) of formamide was stirred at 160° C. until evolution of ammonia ceased (about 24 hr). The reaction mixture was dissolved in 150 ml of tetrahydrofuran and treated dropwise at reflux with 101 ml (1.01 mole) of 10M borane-methylsufide. Reflux was continued for 5.5 hr and the mixture was allowed to stand at room temperature over the weekend. Approximately 200 ml of methanol was added dropwise and the mixture was heated to reflux for 1 hr. Hydrogen chloride gas was bubbled into the mixture until a pH of <1 persisted. The mixture was heated to reflux for 3 hr and filtered. The filtrate was treated with 500 ml of dilute sodium hydroxide and extracted 4 times with ether. The aqueous layer was continuously extracted with chloroform for 24 hr. The chloroform was concentrated to give 22 g of residue. A 20 g sample was dissolved in 80 ml of ethanol. The resulting crystals were recrystallized from methanol-water to give 15 g of crystals, m.p. 197°-199° C.
Reaction SMILES: [ClH:1].N[C:3]1[CH:4]=[CH:5][C:6]([Cl:10])=[N:7][C:8]=1[CH3:9].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>O>[Cl:10][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([S:15]([Cl:1])(=[O:17])=[O:16])=[CH:4][CH:5]=1
Reactant: O=S=O
Reactant: Cl
Reactant: Cc1nc(Cl)ccc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)ccc1S(=O)(=O)Cl
Yield: 67 %

Procedure:
Under ice-cooling, thionyl chloride (4 mL) was added dropwise to water (24 mL) over 20 min. The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, to the concentrated hydrochloric acid (6 mL) was added 5-amino-2-chloro-6-methylpyridine (1.0 g) with stirring under ice-cooling, and a solution of sodium nitrite (0.5 g) in water (2 mL) was added dropwise over 10 min. The reaction mixture was gradually added at 5° C. to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (10 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration, and washed with water to give the title compound as a pale-yellow solid (yield 1.1 g, 67%).
Reaction SMILES: [CH2:1]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1)[C:6](=[O:13])[CH2:7][CH2:8][C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH3:4].C([Sn]([N:42]=[N+:43]=[N-:44])(CCCC)CCCC)CCC.[OH-].[K+]>CC1C=CC=CC=1C>[CH2:1]([N:5]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[NH:44][N:43]=[N:42][N:28]=2)=[CH:19][CH:20]=1)[C:6](=[O:13])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)CCC(=O)O
Reaction time: 2 h

Procedure:
A solution of 8.8 g (22.7 mmol) of 3-methoxycarbonylpropanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 9.8 g (29.5 mmol) of tributyltin azide in 100 ml of o-xylene is heated under reflux for 20 hours. The reaction mixture is then cooled to 20° and 100 ml of 1N potassium hydroxide solution are added thereto. The reaction mixture is stirred thoroughly for 2 hours, and the aqueous phase is separated and acidified with 2N hydrochloric acid. The resin which separates is extracted with ethyl acetate. The crude product, obtained by concentration of the ethyl acetate phase by evaporation, is flash-chromatographed on 500 g of silica gel [toluene/isopropanol/glacial acetic acid (170:30:2)] to yield 3-carboxypropanoic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amide in the form of a light-brown foam that has an Rf value of 0.20 [toluene/isopropanol/glacial acetic acid (170:30:2)]. ##STR8##
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[CH:33]([NH:35][C:36]1[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:46])[CH:42]=3)[N:37]=1)[CH2:32][CH2:31]2>>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:1]([NH:46][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[N:37]=[C:36]([NH:35][CH:33]2[C:34]4[C:30](=[CH:29][CH:28]=[CH:27][C:26]=4[O:25][CH3:24])[CH2:31][CH2:32]2)[CH:45]=[CH:44]3)=[O:2])[CH2:21][CH2:22]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: COCCN1CCC(N)CC1
Product: COCCN1CCC(NC(=O)Nc2ccc3nc(NC4CCc5cccc(OC)c54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-methoxy-ethyl)-piperidin-4-ylamine and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=490.7 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:39]=[CH:38][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.[CH3:40]I>CCCCC.O1CCCC1>[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:38][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:40])[CH:21]=1
Reactant: CI
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), and tetrahydrofuran (10 mL) was added. The product from Example 11, 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts were dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O20.25H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: Brc1nsc2nc3ccccc3n12
Solvent: ClCCl
Product: c1ccc(Nc2nsc3nc4ccccc4n23)nc1
Reaction time: 48 h
Yield: 83.1 %

Procedure:
To a cooled solution of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (0.30 g, 1.17 mmol) in 15 mL of dichloromethane, 2-aminopyridine (0.276 g, 2.93 mmol) was added dropwise and the mixture was allowed to stir for 48 h. The reaction mixture wad diluted with 100 mL of dichloromethane and washed with water (2×30 mL) and then brine (1×25 mL). The organic layer was dried over magnesium sulfate and evaporated to give a yellow solid (0.26 g, 83%) 1H-NMR (CDCl3)δ 6.59 (apparent 5, 1H, pyr-H), 7.12 (apparent br. d, 1H, pyr-H), 7.28 (t, 1H, ArH), 7.38 (t, 1H, ArH), 7.51 (m, 2H, ArH & pyr-H), 7.70 (d, 1H, ArH), 8.28 (d, 1H, pyr-H); m.p. 155.5-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[CH3:16][NH:17][OH:18].[OH-].[Na+]>C(O)C.O>[CH3:16][N+:17]([O-:18])=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: CNO
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=[N+](C)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.7 %

Procedure:
To a stirred suspension of 9.97 g (50.9 mmol) of 2,3,4-trimethoxybenzaldehyde and 4.43 g (53.1 mmol) of N-methylhydroxylamine hydrochloride in 100 mL of ethanol was added a solution of 2.05 g (51.3 mmol) of sodium hydroxide in 15 mL of water. The mixture was stirred at room temperature for 22 h and evaporated in vacuo to remove the bulk of the solvent. The residual solid was taken up in 150 mL of dichloromethane, washed with 50 mL of water and dried over MgSO4. Removal of the solvent afforded 11.31 g of N-methyl-C-(2,3,4-trimethoxyphenyl)nitrone as a white solid. 1H-NMR (CDCl3) d 3.85-3.95 (9H), 6.75 (d, 1H), 7.65 (s, 1H), 9.1 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]C4CCNCC4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[CH:3]1.[CH3:32][N:33](C)[CH2:34]C(O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:32][NH:33][CH3:34])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[CH:3]1
Reactant: CN(C)CC(=O)O
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.188 g), 2-(dimethylamino)acetic acid (0.090 g) and DIPEA (0.362 ml) were dissolved in NMP (2.5 ml) and HATU (0.250 g) was then added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated sodium bicarbonate solution. Organics were dried over sodium sulphate to yield crude. Purification by flash chromatography (10 g SiO2 column, DCM to 5% MeOH in DCM gradient) afforded methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. (59 mg)
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[CH3:17].[OH2:18]>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[C:17]([OH:2])=[O:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Reactant: O
Agent: [K+]
Product: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirring suspension of potassium permanganate (102 g, 0.65 mol) in water (1.4 L) was added 2-fluoro-6-nitrotoluene. The reaction was heated at reflux for 4 h, cooled to room temperature, filtered, and washed with diethyl ether. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 11.81 g (40%).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)([OH:20])[C:2]([F:4])([F:3])[F:1]
Reactant: COc1ccc(Cl)c(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 0.80 mL) was added at 0° C. to a solution of 5-[2-(2-chloro-5-methoxy-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (312 mg, obtained in Example 192, step 2) in THF (20 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (253 mg). Stirring was continued for 72 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=7:3 to 6:4) to give the title compound as a orange amorphous foam (43 mg, 14%). MS (neg. ion, m/e)=414.3 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)=[O:10])=[CH:6][CH:5]=[C:4]([CH2:21][C:22]([O:24]CC)=[O:23])[N:3]=1.[OH-].[Na+].CO.O.Cl>C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)=[O:10])=[CH:6][CH:5]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[N:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cn(C)c3ccccc23)c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cc(C(=O)Nc2ccc(CC(=O)O)nc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetate (859 mg, 2.31 mmol) was dissolved in THF (25 ml). To the resulting solution was added 0.25N NaOH (13.9 ml, 3.47 mmol), followed by stirring at room temperature for 4 hours. Methanol-water (1:1, v/v, 10 ml) was added, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was acidified with 1N HCl (5.0 ml). The crystals thus precipitated were collected by filtration, washed with water, and dried under reduced pressure to give 2-chloro-3-(1-methyl-3-indolylcarbonyl)amino-6-pyridylacetyl acid (702 mg, 88%) as a colorless solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([N:49]4[CH2:50][CH2:51][O:52][CH2:53][CH2:54]4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the amide intermediate, 1 mL of 4N HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give a crude product which was used directly in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[C:8]2([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1)SC.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:40][C:39]1[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:37]([O:36][CH3:35])[CH:38]=1)[C:9](=[O:16])[CH:8]2[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: COc1cc2c(cc1OC)C(CCN1CCN(c3ccccc3OC)CC1)(SC)C(=O)N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(CCN3CCN(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc32)cc1OC
Yield: 57.5 %

Procedure:
In dimethylformamide was suspended 38 mg of sodium hydride. To the suspension were added 285 mg of 5,6-dimethoxy-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-3-methylthio-1,3-dihydro-2(2H)-indolone and 140 mg of 3,4-dimethoxybenzyl chloride. A sodium hydrogencarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was dissolved in ethanol. Separately, an acetone solution containing 2.0 g of Raney nickel was refluxed, and the solvent was removed by decantation. To the residue was added the above prepared ethanol solution, followed by refluxing for 15 minutes. A precipitate was removed by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to 0:1) to obtain 201 mg of the title compound.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)N(C)CCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: C1CSCCN1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCSCC2)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.25 g, 0.67 mmol), thiomorpholine (0.19 mL, 2.0 mmol) and diisopropylethylamine (0.06 mL, 0.67 mmol) in DMPU (3.0 mL) were heated at 135 C for 23 hr. The reaction was cooled to room temperature, neutralized by the addition of TFA and purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.