Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[O:25])[O:16][C:15]2=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1C=C(Cl)C=C(C(OO)=[O:43])C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@@H:17]([CH2:19][NH+:20]([O-:43])[C:21](=[O:33])[CH2:22][CH2:23][C:24]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[O:25])[O:16][C:15]2=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCC(=O)c1ccc(Cl)cc1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: O=C(CCC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a cooled solution (0-5° C.) of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-4-(4-chlorophenyl)-4-oxobutanamide, (1.150 gm, 0.0023 moles) in dichloromethane (150 ml) was added 60% m-CPBA (0.725 gm, 0.0040 moles) and the resulting solution stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue chromatographed over silica gel (100-200 mesh, 40 g). The column was eluted with ethyl acetate (200 ml) followed by a mixture of chloroform:methanol (4:1, 600 ml). Concentration of the combined fractions gave the title N-oxide (0.950 g, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Al+3].[Cl-].[Cl-].[Cl-].[Br:16]Br>CCOCC>[Br:16][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
25 g (0.1322 mol) of 2′,4′-dichloroacetophenone was placed in a three-neck round bottom flask equipped with a magnetic stir bar, reflux condenser, and dropping funnel. Anhydrous ether (30 mL) and AlCl3 (0.20 g) were added. The solution was stoppered and cooled to 0° C. in an ice bath. Br2 (21.13 g, 0.1322 mol) was added dropwise (at a rate of approximately 0.5 mL/min). After addition of Br2 was complete, HBr and the solvent were removed under reduced pressure. The remaining HBr was removed by blowing a stream of nitrogen over the orange oily product. The resulting oil was placed under high vacuum until all the bubbling had ceased. The product was obtained as a viscous orange oil, which solidified upon standing in the refrigerator. Yield: 35.72 g (100%); TLC: 95% Hexanes/5% Acetone, Rf=0.35.
Reaction SMILES: Cl.C1(C2CCN(C[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[C:28]4[CH:31]=[CH:32][CH:33]=[C:26]5[C:27]=4[C:22](=[CH:23][CH:24]=[CH:25]5)[C:21]3=[O:34])CC=2)C=CC=CC=1.[Br:35]CCCCCBr.BrCCCCCCBr>>[Br:35][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[C:26]3[C:27]=2[C:22](=[CH:23][CH:24]=[CH:25]3)[C:21]1=[O:34]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CC=C(c2ccccc2)CC1
Reactant: BrCCCCCBr
Agent: BrCCCCCCBr
Agent: Cl
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of Example 56 but substituting 1,5-dibromopentane for the 1,6-dibromohexane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[N:7]([CH2:20][CH2:21][OH:22])[CH:6]=[CH:5]2.[Br:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([CH3:34])[CH:31]=[C:32](I)[C:25]=12>>[Br:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([CH3:34])[CH:31]=[C:32]([C:10]3[CH:9]=[C:8]4[C:4]([CH:5]=[CH:6][N:7]4[CH2:20][CH2:21][OH:22])=[CH:3][C:2]=3[F:1])[C:25]=12
Reactant: Cn1cc(I)c2c(Br)ccnc21
Reactant: CC1(C)OB(c2cc3c(ccn3CCO)cc2F)OC1(C)C
Product: Cn1cc(-c2cc3c(ccn3CCO)cc2F)c2c(Br)ccnc21

Procedure:
The title compound was prepared from 2-(5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanol (D79) and 4-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (D7) using a similar procedure to that described for D8. LCMS (A): m/z (M+H)+ 388/390, C18H15BrFN3O requires 387/389 (acidic).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]=[C:9]2[C:14](=[O:15])[C:13]3[C:16]([NH2:31])=[C:17]([N:20]=[N:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:12]=3[CH:11]=[CH:10]2)=[CH:3][CH:2]=1.[OH2:32]>>[N+:28]([O-:30])([OH:32])=[O:29].[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]=[C:9]2[C:14](=[O:15])[C:13]3[C:16]([NH2:31])=[C:17]([N:20]=[N:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:12]=3[CH:11]=[CH:10]2)=[CH:3][CH:2]=1
Reactant: O
Agent: Nc1c(N=Nc2ccc([N+](=O)[O-])cc2)ccc2c1C(=O)C(=NNc1ccccc1)C=C2
Product: O=[N+]([O-])O
Yield: 10 %

Procedure:
The preparation of the Levanyl Black involves rolling 5 g of Levanyl Black in about 572 g of water and the preparation of the Nigrosin Black involves rolling 2–3 g of the Nigrosin Black in about 420 g of water. The Nigrosin Black solution should have a pH of 3.0–6.0 which can be obtained with the addition of an appropriate quantity of 10% nitric acid after the Nigrosin Black is rolled. In this example, the order of ingredients is particularly important for obtaining a stable formulation. Experiments have shown that an intermediate silicate formulation should be made in a separate vessel by first adding the acid to about 20 g of water followed by the addition of the alcohol and organic silicate. Next, the contents of the separate vessel should be shaken to hydrolyze the organic silicate, thereby creating the intermediate silicate formulation. The solvent and remaining water should then be mixed into the separate vessel, thereby making a diluted intermediate silicate formulation. The general conclusion is that it is best to dilute the intermediate formulation with a slow evaporating organic solvent such as 1-propanol and water. The reason is that the final formulation will flash-off more slowly during application and, in turn, provide a glossier finish.
Reaction SMILES: C[O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[Al+3].[Cl-].[Cl-].[Cl-].CC(=O)OCC>C(Cl)Cl.Cl>[OH:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCOc1cc([N+](=O)[O-])c(C#N)cc1O
Yield: 35.3 %

Procedure:
To a solution of 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzonitrile (1.5 g) in anhydrous DCM (30 mL) was added anhydrous AlCl3 (6 g) at 0° C. The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was diluted with 1N aqueous HCl (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.5 g of 5-hydroxy-4-(2-methoxyethoxy)-2-nitrobenzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 7.85 (s, 1H), 7.33 (s, 1H), 4.32-4.30 (m, 2H), 3.87-3.84 (m, 2H), 3.50 (s, 3H).
Reaction SMILES: [OH-].[Na+].[N+:3]([N:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[N:17][CH:18]=1)([O-:5])=[O:4]>O.C(O)C>[N+:3]([N:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)CCSc1ccc(CN2CCNC2=N[N+](=O)[O-])cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCSc1ccc(CN2CCNC2=N[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
0.44 g (11 mmol) of sodium hydroxide dissolved in 30 ml water was added to a suspension containing 1.3 g (3.7 mmol) of ethyl 3-[5-(2-nitroiminoimidazolidin-1-ylmethyl)-2-pyridylthio]propionate (4) in 40 ml of ethanol and stirred at room temperature for 1 hour. The ethanol was distilled away under reduced pressure, and 20 ml of water and 30 ml of ether were added to the residues which were then partitioned, and the aqueous layer was adjusted to pH 5 with dilute hydrochloric acid and extracted twice with 70 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel chromatography (ethyl acetate: methanol=1:1) to give 0.6 g of (5) (yield 50%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)C(CC1CC1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-c2c(C(CC3CC3)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
To a suspension of ethyl 2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoate (0.035 g; 0.080 mmol) in a mixture methanol-ethanol (2:1) (2.4 mL) was added a 5% sodium hydroxide solution (1.94 mL; 2.42 mmol) and the reaction mixture was heated to 90° C. for 6 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified with HCl (1N) until pH 2. The white precipitate was filtered and dried to furnish 0.025 g (76%) of the title compound as a white solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[NH:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.F[C:29](F)(F)[C:30]([OH:32])=O>>[CH2:19]([C:18]1[N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[C:6]([OH:5])=[O:7])=[CH:15][CH:14]=2)[C:6](=[O:5])[CH:8]=[C:9]([O:32][CH2:30][CH3:29])[N:23]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCc1nc(OCC)cc(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound is prepared from N-(2'-t-butoxycarbonylbiphen-4-yl)methylvaleramidine and ethyl 3,3-diethocyacrylate (Aldrich) similarly to that in Example 16. The t-butyl ester is hydrolyzed in neat trifluoroacetic acid to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.S([O-])([O-])(=O)=O.O[NH3+:29].O[NH3+].[OH-].[Na+].Cl>O.C(O)(C)C>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:29])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: [NH3+]O
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 2 parts of hydroxylammonium sulfate are suspended at room temperature in 60 parts of isopropanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed netural with water and dried, affording 7 parts of 1,4-diaminoanthraquinone-2-carboxylic acid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=CC(CS(Cl)(=O)=O)=CC=1)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[CH:47][CH:48]=1)(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Product: N#Cc1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (4-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O>C(O)C.[Pt]=O>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Agent: O=[Pt]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reaction time: 3 h

Procedure:
A suspension of give 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzamide (560 mg) and platinum oxide (50 mg) in ethanol (50 mL) was hydrogenated at 50 psi for 3 h. The catalyst was filtered through Celite and the filtrate evaporated to give 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide as a brownish foam; MS (m/z) 256 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:14][C:15]1[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C.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>[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:16]3[CH:17]=[CH:18][C:19]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:20][C:15]=3[CH3:14])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Reactant: Cc1cc(OC(F)(F)F)ccc1B(O)O
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OC(F)(F)F)ccc1-c1ccc2nnc(C(C)C)n2n1

Procedure:
To a microwave reaction tube was added 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine prepared as described in Step 1 above (1.28 mmole), 2-methyl-4-(trifluoromethoxy)phenylboronic acid (1.40 mmole), tetrakis(triphenylphosphine)palladium (0.064 mmole), 2M Na2CO3 (1 mL), and DMF (3 mL). The resulting reaction mixture was heated in the microwave at 130 C for 10 min. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by preparative HPLC to afford 3-isopropyl-6-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:21][CH:22]=2)[CH2:13][CH2:14]1
Reactant: CCC(NC(C)=O)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Product: CCC(NC(C)=O)c1ccc(CN2CCN(c3ccc(F)cc3F)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2,4-difluorophenyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)propyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as pale-brown crystals, m.p.=137-138° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35]CC4C=CC(OC)=CC=4)=[C:31]([Cl:45])[CH:30]=3)(=[O:28])=[O:27])=[CH:22][C:21]=2[CH3:46])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:45][C:31]1[CH:30]=[C:29]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)=[C:21]([CH3:46])[CH:22]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: COc1ccc(COc2ccc(S(=O)(=O)c3ccc(C4CCN(C(=O)OC(C)(C)C)C4)c(C)c3)cc2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)c2ccc(O)c(Cl)c2)ccc1C1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid was added to a solution of 3-{4-[3-chloro-4-(4-methoxy-benzyloxy)-benzenesulfonyl]-2-methyl-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared following the procedure described in Example 6) (0.397 g, 0.6939 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was then evaporated under reduced pressure. The crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.143 g of 2-chloro-4-(3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl)-phenol (white foam) that was transformed in the corresponding hydrochloride salt by addition of a small excess of HCl in 1,4-dioxane. The hydrochloride was recrystallized to afford 0.129 g of a white solid: MP=110.0-112.9° C.
Reaction SMILES: [Si](Br)(C)(C)C.CS(C)=O.[C:10]1([CH2:16][CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[S:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>CC#N>[C:10]1([C:16]2[S:35][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:28][CH:29]=3)=[N:36][CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=S)Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=CCc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CS(C)=O
Product: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Me3SiBr (0.052 mL, 0.384 mmol, 1.1 equiv) and DMSO (0.027 mL, 0.384 mmol, 1.1 equiv) are added sequentially and dropwise to a cold (0° C.) solution of phenylacetaldehyde (42 mg, 0.349 mmol) in CH3CN (0.66 mL), under an argon atmosphere. The resulting mixture is stirred at 0° C. for 50 min, allowed to warm to RT and to stir for 10 min. CH3CN (0.97 mL) is added to the reaction mixture, followed by addition of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thiourea (93 mg, 0.349 mmol). The reaction mixture is heated to reflux for 80 min, allowed to cool to RT and concentrated in vacuo. Purification of the crude product by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 90/10) affords the title compound: ES-MS: 366.0 [M+H]+; single peak at tR=6.33 min (System 1); Rf=0.11 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([OH:26])=O)=[CH:10]2)=[O:5].CN(C)CCCN=C=NCC.Cl.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:44][CH:43]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]([CH3:27])([CH3:28])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([NH:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:47]=1)=[O:26])=[CH:10]2)=[O:5]
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.13 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxylic acid from Example XXXIX, 37.6 mg (0.20 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 8 mg (0.07 mmol) of 4-dimethylaminopyridine are initially charged in DMF. 32.7 mg (0.16 mmol) of tert-butyl 4-aminophenylcarbamate are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CC(=O)C(C)Br
Reactant: Nc1cc(Cl)cnc1N
Solvent: CCO
Product: Cc1nc2c(N)cc(Cl)cn2c1C
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-5-chloropyridine (5.26 g, 36.64 mmol) and 3-bromo-2-butanone (6.2 g, 41.06 mmol) in ethanol (60 ml) was refluxed overnight. After cooling to room temperature, the crystalline product was filtered and washed with ethanol and ether. The crystals were dissolved in methylene chloride and neutralized by aqueous NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. Yield 3.0 g.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3[F:24])=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)[CH:7]=1.[Br-].[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][Zn+])[CH3:31]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.C1C=CC([C]2[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C]2C2C=CC=CC=2)=CC=1.[Fe].C1COCC1>[CH3:26][C:25]([C:12]1[CH:11]=[C:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])[CH:3]=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])([CH3:28])[CH3:27]
Reactant: CCOC(=O)CC[Zn+]
Reactant: COc1ccc(F)c(-c2ccc(COc3cncc(Br)c3)cc2C(C)(C)C)c1
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cncc(OCc2ccc(-c3cc(OC)ccc3F)c(C(C)(C)C)c2)c1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a sealed tube containing 96.A (0.2020 g, 0.455 mmol), bis(dibenzylideneacetone)palladium(0) (0.0141 g, 0.0245 mmol), and CTC-Q-Phos (0.0168 g, 0.0236 mmol) was added dry THF (3 mL). After 5 minutes, 3-ethoxy-3-oxopropylzinc bromide (2.0 mL, 1.00 mmol) (0.5 M solution in THF) was added. After 1 hour, the mixture was heated to 80° C. and monitored with TLC and LC-MS. After 16.5 hours, the reaction was cooled to room temperature, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 96.B which was used without further purification (129.1 mg, 61% yield). MS ESI (pos.) m/e: 466.3 (M+H)+.