Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.O>CN(C)C=O>[CH2:42]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Sodium hydride (60%, oily, 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N,N-dimethylformamide (5 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. Benzyl bromide (0.10 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazolyl methoxy]benzyl]-4-pheny-3-pyrrolyl]propionate (419 mg, yield: 95%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 126–127° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1>>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=[N+]([O-])c1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
1-(2-Bromoethyl)-2-nitrobenzene (1.5 g, 6.52 mmol) and 4-amino-1-benzylpiperidine (3.0 ml, 14.71 mmol) were combined. Mixture was heated neat at 100° C. and held with stirring for 17 hours. Mixture was cooled to room temperature. Residue was triturated in 30 mL diethyl ether. Solids were filtered off, washed with diethyl ether and discarded. Filtrate was concentrated. Silica gel chromatography on the residue eluting 2M ammonia in methanol-dichloromethane afforded the title compound as brown oil in 81% yield. MS (M+H)+=340.4.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:34](S(C(F)(F)F)(=O)=O)[S:35]([C:38]([F:41])([F:40])[F:39])(=O)=[O:36]>ClCCl.N1C=CC=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([O:21][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:34])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (200 mg, 0.43 mmol) in dichloromethane (10 mL) and pyridine (0.35 mL) was added Tf2O (0.1 mL, 0.87 mmol) at −78° C. The temperature was slowly raised to 0° C. The mixture was stirred at 0° C. for 2 hours, quenched with slowly addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to provide a brown colored solid. The obtained residue was purified by flash chromatography to provide the desired product (200 mg, 77%). LCMS-ESI+ (m/z): 602.0, 604.0 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClC1C=C(Cl)C(Cl)=CC=1Cl.[Cl-:22].[Cl-:23].[Cl-:24].[Al+3]>C1(C)C(C)=CC=CC=1>[Cl:22][C:7]1[CH:8]=[CH:9][C:4]([OH:3])=[C:5]([Cl:23])[C:6]=1[Cl:24]
Reactant: ClC(Cl)(Cl)Oc1ccccc1
Reactant: [Cl-]
Agent: Clc1cc(Cl)c(Cl)cc1Cl
Agent: [Al+3]
Solvent: Cc1ccccc1C
Product: Oc1ccc(Cl)c(Cl)c1Cl
Yield: 97 %

Procedure:
A mixture of trichloroanisole (0.1 g mol; 21.15 g) and 1,2,4,5-tetrachlorobenzene (10 g) in xylene (80 ml) was heated at 80° C. with aluminium trichloride (0.05 mole; 6.65 g) for five hours. Trichlorophenol was isolated in 97% yield (based on trichloroanisole) as described in Example I below. Unchanged tetrachlorobenzene, together with xylene self condensation product (total 13.25 g) was isolated from the neutral product fraction after solvent removal.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)C)=[CH:16][CH:15]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:13]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 246.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 1-(4-aminophenyl)ethanone (1.19 g, 1.19 mmol) in ethanol (3 mL). 2-oxo-1-p-tolylpyrrolidine-3-carboxylic acid 0.644 g (quantitative) was obtained as a bright yellow solid.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>COCCOCCOC>[CH2:20]=[C:21]([C:26]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: OCC(F)(F)F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: COCCOCCOC
Solvent: CCCCN(CCCC)CCCC
Product: C=C(C(F)(F)F)C(F)(F)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
A 100 ml flask is charged with tributylamine (15 g), diglyme (20 ml) in a dry box. 2,2,2-Trifluoroethanol (8.05 g) is added to the mixture. CH2═C(CF3)CF2OSO2F (19.5 g) is added dropwise while the mixture is cooled in an ice-water bath. The resulting mixture is stirred at room temperature for 3 hours. The mixture is then distilled to give a liquid, which is redistilled (spinning band column) giving 5.8 g CH2═C(CF3)CF2OCH2CF3, b.pt. 85–86° C., a yield of 30%. Less pure fractions are not included in the yield calculation.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31].[I-].[Na+]>CO>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(=O)N3CCCCC3)ccc-2c(C(=O)OCC)c1N

Procedure:
A mixture of 0.96 g (2.5 mmol) of diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium, 50 ml of methanol, 0.4 g (2.5 mmol) of N-chloroacetyl-piperidine and 20 mg of sodium iodide is heated at reflux for 20 hours. Thereafter, the mixture is concentrated and the residue is chromatographed on silica gel. Elution with isohexane: ethyl acetate 1:1 gives 0.42 g (35% of theory) of the title compound of m.p. 153-155° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[N:5][C:4]=1[N+:12]([O-:14])=[O:13].S(=O)(=O)(O)[OH:16]>>[Br:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]([NH2:11])=[O:16])[CH:6]=[N:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: N#CCCn1cnc([N+](=O)[O-])c1CBr
Product: NC(=O)CCn1cnc([N+](=O)[O-])c1CBr

Procedure:
3-[5-(Bromomethyl)-4-nitro-1H-imidazol-1-yl]propanenitrile (115) (680 mg, 2.62 mmol) was treated with 90% sulphuric acid (5 mL) at 65-70° C. for 1 hour, before being poured onto ice. After a standard ethyl acetate/NaHCO3 workup, the crude product obtained was precipitated from THF by the addition of i-Pr2O to give 3-[5-(bromomethyl)-4-nitro-1H-imidazol-1-yl]propanamide (116) (420 mg, 58%) as an off-white solid, m.p. 139-141° C. 1H NMR (d6-DMSO) δ 7.90 (s, 1H), 7.44 (br, 1H), 7.00 (br, 1H), 5.06 (s, 2H), 4.32 (t, J=6.8 Hz, 2H), 2.70 (t, J=6.8 Hz, 2H). LR-MS (APCI +ve): m/e 277.5/279.5 (1:1, M+1).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:16])[CH:10]([NH2:15])[C:11](=O)[CH2:12][CH3:13])=[CH:5][CH:4]=1.[O-:17][C:18]#[N:19].[K+]>O>[CH2:12]([C:11]1[NH:19][C:18](=[O:17])[NH:15][C:10]=1[CH:9]([OH:16])[C:6]1[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=1)[CH3:13]
Reactant: N#C[O-]
Reactant: CCC(=O)C(N)C(O)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCc1[nH]c(=O)[nH]c1C(O)c1ccncc1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
In 100 ml water is dissolved 29.0 g (0.11 mol) of 1-(4-pyridyl)-1-hydroxy-2-amino-3-ketopentane dihydrochloride and 17.9 g (0.22 mol) of potassium cyanate. The solution is warmed to 50° C. for 10 minutes and then allowed to stand at room temperature for 10 hours, cooled and the solid collected to give the title compound; m.p. 234°-36°.
Reaction SMILES: O=[C:2]([CH3:16])[CH2:3][CH:4]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:2]1[O:15][C:10]([C:11]([F:14])([F:13])[F:12])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C)oc1C(F)(F)F
Yield: 69.5 %

Procedure:
To a solution of ethyl 4-oxo-2-(2,2,2-trifluoroacetyl)valerate (40 g, 167 mmol) in toluene (250 ml) was added p-toluenesulfonic acid (3 g, 16 mmol) and the mixture was heated under reflux overnight in a Dean-Stark apparatus under dehydrated conditions. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give ethyl 5-methyl-2-(trifluoromethyl)-3-furancarboxylate (25.8 g, 70%).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:23]([CH2:27]Br)[C:24]([NH2:26])=[O:25]>>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:23]([C:24]([NH2:26])=[O:25])[CH2:27]2)[CH:17]=[CH:16][CH:15]=1)(=[O:21])[CH3:20]
Reactant: NC(=O)C(Br)CBr
Reactant: CC(=O)Nc1cccc(NCCNCc2ccccc2)c1
Product: CC(=O)Nc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-[3-[[2-[(phenylmethyl)amino]ethyl]amino]phenyl]acetamide (25.6 g, 90.4 mmol) with 2,3-dibromopropanamide (41.8 g, 180.8 mmol) to obtain the titlecompound.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.[CH3:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23]=1[C:39]1[O:40][CH:41]=[CH:42][N:43]=1>C(Cl)(Cl)(Cl)Cl.O>[Br:13][CH2:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23]=1[C:39]1[O:40][CH:41]=[CH:42][N:43]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=c1c(CBr)c(-c2ncco2)n(-c2ccccc2)c2ncccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of 2,2′-azobis(2-methylpropionitrile) (AIBN, 43.4 mg, 0.265 mmol), N-bromosuccinimide (345 mg, 1.94 mmol) and 3-methyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (535 mg, 1.76 mmol) in carbon tetrachloride (22.0 mL) was heated at 90° C. for 2 hr. The reaction was cooled to 25° C. and sat overnight. The reaction was diluted with water (30 mL) and extracted into methylene chloride (2×50 mL). The combined organics were then washed with a saturated aqueous solution of sodium bicarbonate (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and methanol, treated with silica gel, re-concentrated and dried in vacuo. Flash chromatography (40 g, 15%-40% ethyl acetate-hexanes) gave 3-bromomethyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (321.7 mg, 47.7%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:32][CH3:33])=[C:14]([C:16](=[N:30][OH:31])[CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1>[C:34]([O:31][N:30]=[C:16]([C:14]1[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][C:13]=1[NH:32][CH3:33])[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NO
Agent: CN(C)c1ccncc1
Product: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NOC(C)=O
Yield: 85 %

Procedure:
A solution of methyl 4-[2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]-2-(hydroxyimino)ethyl]-3-methoxybenzoate (79.9 mg), 4-(dimethylamino)pyridine (22 mg), and acetic anhydride (0.17 ml) in dischloromethane (11 ml) was stirred under a nitrogen atmosphere for 15 hours. The solution was diluted with dischloromethane, washed with 5% w/v sodium hydrogen sulfate, water, and brine, then dried (MgSO4), and evaporated to give methyl 4-[2-(acetoxyimino)-2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]ethyl]-3-methoxybenzoate (74.1 mg, 85%) as a pink solid; NMR (80 MHz, CDCl3): 1.2-1.8 [8H, (CH2)4 ], 2.1 (s, 3H, CH3CO), 3.0 (d, 3H, NCH3), 3.3. (dd, 2H, CH2NH), 3.9 (2s, 6H 2×OCH3), 4.3(s, 2H, ArCH2), 5.8 (broad, 1H, NHCO), 6.7(d, 1H), 7.0 (d, 1H), 7.4-7.6 (m, 3H), 7.8 (d, 1H), 8.5 (broad, 1H, CH3NH).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:12]([Si:15]([CH3:18])([Cl:17])[Cl:16])(Cl)Cl>>[C:1]1([C:12]([Si:15]([CH3:18])([Cl:17])[Cl:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: C[Si](Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C[Si](Cl)(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1 above, 50.4 ml (564 mmol) of benzene and 2.92 g (21.9 mmol) of aluminum chloride were alkylated with 10.0 g (43.0 mmol) of (trichloromethyl)methyldichlorosilane under dry nitrogen atmospheric pressure for 5 hours at room temperature. The aluminum chloride catalyst was quenched with PoCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, recrystallization from chloroform yielded 3.58 g of (triphenylmethyl)methyldichlorosilane (mp: 170-172° C., yield; 23%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:40]=[CH:41][CH:42]=1)[CH2:11][N:12]([C@@H:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)[C:13]([C:15]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[C:18]([C:24](O)=[O:25])=[CH:17][C:16]=1[C:27]([OH:29])=[O:28])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:43][O:44][C:45]1[CH:46]=[CH:47][C:48]([S:51]([NH:54][C:24]([C:18]2[CH:17]=[C:16]([C:27]([OH:29])=[O:28])[C:15]([C:13]([N:12]([CH2:11][C:10]3[CH:40]=[CH:41][CH:42]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[C@@H:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)=[O:14])=[CH:20][C:19]=2[C:21]([OH:23])=[O:22])=[O:25])(=[O:53])=[O:52])=[CH:49][CH:50]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NC(=O)c2cc(C(=O)O)c(C(=O)N(Cc3cccc(Oc4ccccc4)c3)[C@H]3CCCc4ccccc43)cc2C(=O)O)cc1
Reaction time: 8 h

Procedure:
The product from Example 36B (114 mg, 0.2 mmol), 4-methoxybenzenesulfonamide (37 mg, 0.2 mmol), DMAP (25 mg, 0.2 mmol), and EDCI (78 mg, 0.4 mmol) were combined in THF (10 mL) at room temperature. After stirring overnight, the mixture was concentrated under reduced pressure and CH2Cl2 (20 mL) was added. The mixture was washed with water and the organic layer concentrated under reduced pressure. The residue was purified via HPLC to provide the title compounds. 1H (500 MHz; DMSO-d6) δ6.4-8.6 (m, br., 20H) 5.0 (m, 1H) 4.7 (m, 1H) 4.1 (m, 1H) 3.5 (br, 3H) 1.4-2.7 (m, 6H); MS (M+H)+735.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>CN(C=O)C>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[CH2:21][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CN(C)C(=O)CCl
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(=O)N(C)C)c(OC)c1
Yield: 46.4 %

Procedure:
Methyl 4-hydroxy-3-(methyloxy)benzoate (methyl vanillate, Aldrich) (3.85 g, 21.1 mmol) and potassium carbonate (2.92 g, 21.1 mmol) in DMF (10 mL) was treated at RT with 2-chloro-N,N-dimethylacetamide (Merck) (2.18 mL, 21.1 mmol) and the mixture was stirred over the weekend. The mixture was partitioned between ethyl acetate and 2M HCl. The organic phase was washed with, 2M HCl, saturated sodium bicarbonate solution (turns lightly coloured), acid (loses colour), brine, dried (MgSO4), and evaporated under reduced pressure, to give the product contaminated with starting material (5.0 g). The mixture was therefore re-dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and 2-chloro-N,N-dimethylacetamide (1 mL, 10 mmol) for another day. The mixture was then partitioned between ethyl acetate and 2M HCl and treated as above. The filtrate was evaporated to give a solid (2.614 g) which was loaded in chloroform to a silica cartridge (70 g) and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane gradient over 30 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.4 g, 25%) as a white solid. LCMS (System A) RT=0.69 min, ES+ve m/z 268 (M+H)+.
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:15]=2[CH:16]=[C:17]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C(O)(=O)C>CCOC(C)=O.CO.Br[Zn]Br.[Pd]>[N:10]1[NH:9][N:8]=[C:12]([NH:13][C:14]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:15]=2[CH2:16][CH:17]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)[CH:11]=1
Reactant: O=C(O)C1CC(=Cc2cc(Cl)ccc2Nc2cnnn2Cc2ccccc2)C1
Agent: [Pd]
Agent: Br[Zn]Br
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)C1CC(Cc2cc(Cl)ccc2Nc2cn[nH]n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
To a solution of 3-(2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzylidene)cyclobutanecarboxylic acid 7 g (75 mg, 0.19 mmol) and dibromozinc (17.1 mg, 0.076 mmol) in EtOAc (2 mL) and MeOH (2 mL) was added 10% Pd on C [wet Degussa type] (40 mg, 0.038 mmol). The reaction was then flushed with hydrogen via vacuum/hydrogen cycles (3×) and the mixture stirred under a hydrogen atmosphere for 2 h at room temperature. Additional 10% Pd on C [wet Degussa type] (40 mg, 0.038 mmol) was added and stirred under hydrogen for a further 1 h. Acetic acid (23 mg, 21.60 μL, 0.38 mmol) was then added and mixture stirred under hydrogen overnight. Additional acetic acid (22 mg, 21.60 μL, 0.38 mmol) was added and stirred under hydrogen atmosphere again overnight. The reaction mixture was then filtered through celite washing through with methanol. The filtrate was concentrated and the material purified by FractionLynx to afford the title compound I-28 as a white solid (1.5 TFA salt) (4.0 mg, 3.9% yield). 1H NMR (500 MHz, d6-DMSO) δ 7.78 (1H, brs), 7.59 (1H, brs), 7.46 (1H, brs), 7.10-7.12 (1H, m), 7.06 (1H, d), 2.87-2.94 (1H, m), 2.72 (2H, d), 2.50-2.55 (1H, masked signal), 2.18-2.25 (2H, m), 1.84-1.90 (2H, m). MS m/z: 307.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH2:27])[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH:27][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:26]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
4-Nitrobenzaldehyde (0.302 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give an orange solid. Recrystallization from ethyl acetate gave the product (290 mg), mp 198-199° C.