Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:16]2[S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl.[NH+]1C=CC=CC=1>O>[CH:14]1[C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17][C:16]=2[C:11]([C:4]2[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])=[CH:12][CH:13]=1
Reactant: COc1cccc(OC)c1-c1cccc2c1sc1ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1cccc(O)c1-c1cccc2c1sc1ccccc12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
4-(2,6-Dimethoxyphenyl)-dibenzothiophene (9.00 g) and pyridinium hydrochloride (20 g) were placed in the 100 mL round-bottom flask, equipped with a magnetic stirrer. The flask was immersed in the pre-heated oil bath (220° C., 1 hour), cooled down to room temperature and dissolved in 200 ml of water. The solution was extracted with ethyl acetate (4×50 mL), organic fractions were combined, dried over sodium sulfate, filtered and evaporated, providing 2-(dibenzo[b,d]thiophen-4-yl)benzene-1,3-diol (7.2 g, white solid).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]>CO.[Ni]>[Cl:1][C:2]1[C:3]([C:12]([F:13])([F:15])[F:14])=[CH:4][CH:5]=[C:6]([Cl:11])[C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1c(Cl)ccc(C(F)(F)F)c1Cl
Agent: [Ni]
Solvent: CO
Product: Nc1c(Cl)ccc(C(F)(F)F)c1Cl

Procedure:
Hydrogenation of 2,4-dichloro-3-nitro-benzotrifluoride (5.0 g, 19.2 mmol; ABCR, Karlsruhe/Germany) in 100 ml MeOH in the presence of 1 g Raney-nickel, filtration and concentration of the filtrate gives the title compound: TLC: Rf=0.67 (EE).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.CO[CH:16]([N:19]([CH3:21])[CH3:20])OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:16]/[N:19]([CH3:21])[CH3:20])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3.62 g of 1-(4-bromo-2-nitrophenyl)ethanone and 5.3 g of (dimethoxymethyl)dimethylamine was stirred at 90° C. for 4 hours. The reaction mixture was cooled to room temperature and the precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether and dried under reduced pressure to obtain 3.93 g of (2E)-1-(4-bromo-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([Cl:11])[CH:3]=1.[NH:12]([C:14](=[S:16])[NH2:15])[NH2:13].P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:16][C:14]([NH2:15])=[N:12][N:13]=2)=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc(Br)cc2Cl)s1
Temperature: 78 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To an ice-cooled mixture of 4-bromo-2-chlorobenzoic acid (3 g, 12.74 mmol) and hydrazinecarbothioamide (2.17 g, 23.81 mmol) was added phosphorous oxychloride (3.56 mL, 38.2 mmol) slowly. The mixture was heated at 78° C. overnight. After cooling to 0° C., ice water was added. The mixture was vigorously stirred for 1 h. The resulting precipitate was filtered and washed with water then re-suspended in a saturated NaHCO3 solution and water (1:1) for 1 h. The solid was filtered, washed with water, and concentrated in vacuo to give 5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (2.4 g, MS: 291.8 [M+H+].)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.BrC1C=C(C=CC=1)C=O.[I-].C[N+]1C=CN(C)C=1.[H-].[Na+]>O1CCOCC1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[CH:2]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cn1cc[n+](C)c1
Agent: O=Cc1cccc(Br)c1
Agent: [H-]
Solvent: C1COCCO1
Product: COc1cc2cncnc2cc1OC

Procedure:
The lead compound 4-(3′-bromobenzoyl)-6,7-dimethoxyquinazoline WHI-P164 was synthesized by reacting 4-chloro-6,7-dimethoxyquinazoline 5 with the commercially available 3-bromobenzaldehyde in the presence of 1,3-dimethylimidazolium iodide and sodium hydride in refluxing dioxane for 4 hours (Scheme 2) (32,33). The remaining 6,7-dimethoxyquinazoline derivatives were synthesized by condensing 4-chloro-6,7-dimethoxyquinazoline 5 with the corresponding substituted anilines as shown in Scheme 3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)cc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.04 mmol, Step-1, single enantiomer) and isobutyryl chloride (14 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[CH:11]1([CH2:14][C:15](O)=[O:16])[CH2:13][CH2:12]1.C1(N=C=NC2CCCCC2)CCCCC1.C1(=O)CCCCC1=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:11]1([CH2:14][C:15]([CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[O:16])[CH2:13][CH2:12]1
Reactant: O=C(O)CC1CC1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C1CCCCC1=O
Solvent: ClCCl
Product: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
5,5-Dimethyl-1,3-cyclohexanedione (1.051 g, 7.5 mmol, 1.5 eq), cyclopropylacetic acid (500.6 mg, 5.0 mmol), and 4-dimethylaminopyridine (916.3 mg, 7.5 mmol, 1.5 eq) were dissolved in 10 mL of CH2Cl2, cooled to 0° C. in an ice bath. A solution of N,N′-dicyclohexylcarbodiimide (1.238 g, 16.0 mmol, 1.2 eq) in 5 mL of CH2Cl2 was added dropwise over two minutes to the cyclohexanedione solution. The reaction mixture was then stirred at 0° C. for 10 minutes and at room temperature for 16 hours. The reaction mixture was then filtered and the filtrate purified by column chromatography (hexane to 30% EtOAc/hexane) to yield 1.022 g (92% yield) 2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:25][OH:26])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.CS(C)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1cc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Yield: 77.9 %

Procedure:
To a solution of 4-[9-chloro-6-(hydroxymethyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl]-3-methylbenzamide (390 mg, 1.05 mmol) in acetonitrile (11 mL) and dimethylsulfoxide (2.2 mL) was added Dess-Martin reagent (534 mg, 1.26 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 3 h and diluted with aqueous sodium bicarbonate and aqueous sodium thiosulfate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound as a yellow solid (302 mg, 0.818 mmol, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[F:13][C:14]([F:20])([F:19])[CH2:15][N:16]=[C:17]=[S:18]>C(#N)C>[F:13][C:14]([F:20])([F:19])[CH2:15][NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1
Reactant: N#CCCCCn1ccc(N)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: N#CCCCCn1ccc(NC(=S)NCC(F)(F)F)n1

Procedure:
To a solution of 5-(3-aminopyrazol-1-yl)valeronitrile (7.0 g.) in acetonitrile (25 ml.) was added 2,2,2-trifluoroethylisothiocyanate (6.02 g.). After 15 minutes the solvent was evaporated in vacuo to give 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeronitrile as a white crystalline solid, m.p. 96°-98°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].CN(C=O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-ethoxy-3-(4-nitrophenyl)acrylate containing 3.6 wt % DMF (26.07 g corrected, 98.3 mmol) was dissolved in IMS (500 ml) and a solution of NaOH (1.44 g, 36.1 mmol) in water (260 ml) was added. The resulting mixture was stirred at ambient temperature for 18 hr then acidified with 1M HCl (120 ml) and the resulting solid collected by filtration, washed with water (2×100 ml) and suction dried on the filter for 30 mins, followed by
Reaction SMILES: [CH3:1][O:2]C1C=CC=C(OC)C=1.COC1C=CC2C(=CC(OC)=CC=2)C=1.[NH:25]1[C:32](=[O:33])[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[S:27]>>[CH3:1][O:2][CH:31]1[C:29](=[O:30])[NH:28][C:26](=[S:27])[NH:25][C:32]1=[O:33]
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: COc1cccc(OC)c1
Agent: COc1ccc2ccc(OC)cc2c1
Product: COC1C(=O)NC(=S)NC1=O

Procedure:
The Birch reduction products of 1,3-dimethoxybenzene and of 2,7-dimethoxynaphthalene each react with thiobarbituric acid to form the conjugated methoxy-thiobarbituric acid dyes as shown in FIG. 13. For this reaction, no solvent is used. The reactants were melted at 145° C. for 15 min. Methanol condensing at the walls of the flask showed successful reaction. Purification was carried out by simple filtration over a short column of SiO2 with CH2Cl2. Yields were typically around 60%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc2cccc(O)c2n1
Product: COc1ccc(C=Cc2ccc3cccc(O)c3n2)cc1
Temperature: 180 °C

Procedure:
A mixture of 8-hydroxyquinaldine (9.93 g) and p-anisaldehyde (20 mL) is heated at 180° C. overnight. The reaction is then cooled to room temperature and vacuum distilled. Once the majority of the p-anisaldehyde is distilled off (below 100° C.), the residue remaining in the flask is taken up in hot 95% EtOH. Any undissolved material is filtered off. H2O is added to the EtOH filtrate and the product is obtained as a yellow solid (3.42 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6].[H][H]>[Pd].C(OCC)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH:19]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To 26.6 g of 2-methoxy-5-nitro-N-(4-trifluoromethylbenzyl)benzamide were added 270 ml of ethyl acetate and 2.6 g of 10% palladium on carbon under an atmosphere of argon, then argon was replaced with hydrogen gas, and the mixture was stirred for 8 hours at room temperature under an atmosphere of hydrogen gas. Catalyst was filtered through Celite(Hyflo Super-cel) and, after washed the collected material well with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue obtained was purified by means of column chromatography (silica gel, ethyl acetate) to obtain 24.5 g of 5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][N:4]=1.[N-:10]=[N+:11]=[N-:12].CC1C=CC=C2C=1C(C)=C(C)C(C)=N2>C(Cl)Cl>[N:10]([CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][N:4]=1)=[N+:11]=[N-:12]
Reactant: ClCc1cc(Cl)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1nc2cccc(C)c2c(C)c1C
Solvent: ClCCl
Product: [N-]=[N+]=NCc1cc(Cl)ccn1

Procedure:
The starting material may be obtained as follows. Reaction of 2-chloromethyl-4-chloropyridine with excess tetramethylquinoline azide in CH2Cl2 at ambient temperature for 24 hours gave 2-azidomethyl-4-chlorpyridine. n.m.r. in CDCl3 :-4.5(s, 2H); 7.3(m, 2H); 8.5(d, 1H). Reduction of this compound in MeOH in the presence of 2 equivalents of acetic anhydride with Raneyl nickel at ambient temperature for 30 minutes gave, after purification by silica gel chromatography, 2-acetylaminomethyl-4-chloropyridine, n.m.r. in CDCl3 :-2.1(s, 3H); 4.56(d, 2H); 7.3(m, 2H); 8.48(d, 2H). Reaction of the compound with excess dimethyl sulphate for 30 minutes at 40° gave 2-acetylaminomethyl-4-chloro-1-methylpyridinium methyl sulphate, n.m.r. in solvent F:-2.0(s, 3H); 3.44(s, 3H9; 4.3(s, 3H); 4.7(s, 2H); 8.2(m, 2H); 9.04(d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([O-:19])(=[O:18])=[O:17].[Na+:20]>[Cl-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([O-:19])(=[O:18])=[O:17].[Na+:20]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Product: COCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Reaction time: 1 h
Yield: 87 %

Procedure:
To 30 ml of 2-methoxyethylamine, 27.5 g (0.1 mol) of sodium 2-chloro-5-nitrobenzenesulfonate was added. The reaction mixture was heated on a steam bath with stirring for 1 hour. After cooling, 100 ml of a saturated aqueous sodium chloride solution was added to the mixture. The crystals thus-precipitated were collected by filtration and washed with acetone to obtain about 30 g (yield: 87%) of sodium 2-(2-methoxyethylamino)-5-nitrobenzenesulfonate. This compound (30 g) was suspended in 100 ml of dimethylformamide. To the mixture anhydrous potassium carbonate (20 g) and methoxyethyl bromide (21g) were added, and heated on a steam bath with stirring for 1 hour. The reaction mixture was added to 100 ml of water and the insoluble materials were removed by filtration. To the filtrate an aqueous hydrochloric acid was added to render an acid condition. The crystals thus-precipitated were collected by filtration to obtain about 21 g (yield: 60%) of sodium 2-bis(2-methoxyethyl)amino-5-nitrobenzensulfonate. Melting Point: 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:20][CH:19]3[CH:14]([CH2:15][CH2:16][C:17]4[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:18]=43)[CH2:13]2)=O)=[CH:4][CH:3]=1.B.C1COCC1.[ClH:35]>C1COCC1>[ClH:35].[ClH:35].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:20][CH:19]3[CH:14]([CH2:15][CH2:16][C:17]4[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:18]=43)[CH2:13]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1OC)CCC1CN(C(=O)CCc3ccc(N)cc3)CC21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)CCC1CN(CCCc3ccc(N)cc3)CC21
Temperature: 0 °C
Yield: 57 %

Procedure:
A suspension of the compound of example 15 (2.6 g, 6.8 mmole) in 35 mL dry THF was stirred under N2 at room temperature as BH3.THF (1M solution, 26.7 mL) was added. The reaction mixture was stirred at reflux for 21/2 hrs. After cooling to 0° C., 30 mL methanolic HCl was added. The reaction mixture was stirred at reflux for 6 hours and at room temperature for 18 hours. The solution was evaporated (in vacuo) to dryness and water was added. After two neutral Et2O extracts, the aqueous layers were basified with 1N KOH and extracted three times with CH2Cl2. The combined basic extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, evaporated, converted to the HCl salt, and dried (in-vacuo) to obtain a gray foam which was crystallized from Et2O/EtOH to yield 1.71 g white solid (57%); mp 233°-5° C.; M+ 366 .
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([S:11]([CH3:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([C:5]1[CH:10]=[C:9]([S:11]([CH3:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([NH2:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(C)(C)C)cc1S(C)=O

Procedure:
15.5 g 5-tert-butyl-1-methanesulphinyl-2-methoxy-3-nitro-benzene in 300 ml of ethyl acetate are added 3.0 g 10% palladium-(II)-hydroxide on charcoal and the mixture is hydrogenated for 16 hours at 3 bar hydrogen pressure. Then the hydrogenation catalyst is filtered off through kieselguhr and washed with 100 ml of ethyl acetate. The solvent is eliminated in vacuo and the residue is extracted from n-pentane.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>[Cl-].[Na+].O.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].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(OCC)C>[N:34]1([C:2]2[CH:33]=[CH:32][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[CH2:10][CH2:9][N:8]3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:4][CH:3]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(N3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
1-(4-Bromobenzyl)-6-phenylmethoxy-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.82 g, 1.6 mmol) and piperidine (0.17 g, 1.96 mmol) are placed in a 100 ml round bottom flask containing anh. toluene (50 mL) under nitrogen. NaOtBu (0.22 g, 2.3 mmol), Pd(dba)2 (0.029 g, 2 mol %) and P(o-tolyl)3 (0.02 g, 6 mol %) are added, and the mixture heated to reflux overnight. The reaction is cooled to RT and treated with brine and ethyl ether. The organic layer is dried over MgSO4 and purified by column chromatography (SiO2, hexanes/ethyl acetate, 6:1) to yield the title compound (0.40 g, 49% yield): ES-MS (m/z) 507 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:12]([CH3:16])=[C:13]([Cl:15])[CH:14]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:15][C:13]1[C:12]([CH3:16])=[C:6]([C:5]([O:17][CH2:18][CH3:19])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:14]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8]
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)=O)c1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1OCC

Procedure:
3-Acetyl-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (0.2 g, 0.7 mmol) was treated with sodium tetrahydroborate (0.032 g, 0.84 mmol) in methanol (6 mL) at room temperature for 1 h. The mixture was diluted with water, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and filtered, concentrated to give the desired product. LCMS calculated for C14H21ClNO3 (M+H)+: m/z=286.1; Found: 286.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([Br:17])[C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=O)[O:25]C(C)(C)C)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.CN(C)C1C=CN=CC=1>[C:19]([O:23][C:24](=[O:25])[NH:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([F:18])[C:11]=1[Br:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Nc1cc(F)c(OCc2ccccc2)c(F)c1Br
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(OCc2ccccc2)c(F)c1Br
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of 4-benzyloxy-2-bromo-3,5-difluorophenylamine (3.33 g) in THF (35 mL) were added di-tert-butylcarbonate (6.95 g) and 4-dimethylaminopyridine (130 mg), and the mixture was heated under reflux for 2 hours. The reaction mixture was allowed to stand for cooling to room temperature, and concentrated. The residue was diluted with ethyl acetate and washed with 0.5N hydrochloric acid and saturated aqueous brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give (4-benzyloxy-2-bromo-3,5-difluorophenyl)carbamic acid tert-butyl ester (3.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]2)=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=1)#[N:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)C1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)C1
Yield: 16 %

Procedure:
5-Amino-3-(N-methylpyrrolidin-3-yl)-1H-indole and 4-chloro-3-nitrobenzonitrile were used. Sodium acetate was used as base, acetic acid was used as solvent, and the reaction was heated at reflux for 5 hours. Column chromatography afforded the title compound (16%) as a red amorphous solid: Rf =0.35 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ 147.4, 137.0, 135.8, 132.1, 131.4, 128.2, 127.8, 122.2, 120.4, 120.3, 118.2, 117.2, 117.1, 112.7, 98.9, 62.7, 56.3, 42.4, 35.0, 32.3; HRMS calculated for C20H19N5O2 361.1541, found 361.1500.