Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)C(C)C)(C)C.[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCn1cccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 1H-pyrazole (13.6 g, 200 mmol) and N,N-diisopropylethylamine (68 mL, 400 mmol) in dichloromethane (150 mL), 2-methoxyethoxymethyl chloride (24.9 mL, 220 mmol) was added with cooling on ice. The reaction solution was stirred at room temperature for 2 hours, and an aqueous sodium hydrogencarbonate solution (500 mL) was then added to the reaction solution, followed by extraction three times with dichloromethane (500 mL). The organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:1) to yield the title compound (29.9 g, 96%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(Br)cc1CO
Solvent: CCOCC
Product: Cc1ccc(Br)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 181.2 %

Procedure:
24.4 g (121 mmol) of 5-bromo-2-methylbenzyl alcohol was dissolved in 200 ml of anhydrous diethyl ether, and to the resulted solution was dropped 16.4 g (60.7 mmol) of phosphorus tribromide under ice cooling. The mixture was stirred further for 3 hours under ice cooling, then, the reaction solution was poured into ice water, then, separated. The organic layer was washed with water, saturated sodium bicarbonate solution and saline sequentially, dried over anhydrous magnesium sulfate, then, concentrated to obtain 29.1 g (110 mmol) of 5-bromo-2-methylbenzyl bromide in the form of brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([NH:8][CH:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:7])[C:15]([F:19])=[CH:14][N:13]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(N)c1ccc(F)cc1
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(F)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 4-fluoro-α-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce (±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=2.3 Hz), 7.37-7.33 (dd, 2H, J=5.4 and 8.4 Hz), 7.04 (t, 2H, J=8.4 Hz), 5.35-5.31 (m, 2H), 1.60 (d, 3H, J=6.4 Hz); LCMS: ret. time: 32.90 min.; purity: 98%; MS (m/e): 270 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.0 g, 52.6 mmol, of 4-amino-1-benzyl-piperidine in 150 ml of dichloromethane was added 1.36 g (53 mmol) of benzene sulfonylchloride. The solution was stirred for 1 hour at room temperature, diluted with 500 mL of dichloromethane and washed with 5% aqueous sodium hydroxide followed by water and brine. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 16.6 g of product as an oil. The compound was used without further purification.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([Br:12])=[CH:14][CH:15]=1)=[O:9]
Reactant: COC(=O)C(=O)Cl
Reactant: Brc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 37 %

Procedure:
To a suspension of AlCl3 (3.20 g, 24 mmol) in 100 mL DCM at 0° C., methylchloroglyoxylate (2.2 mL, 24 mmol) was added. The resulting solution was stirred for 5 min., after which 1-bromo-naphthalene (5 g, 24 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-30% EtOAc/Hex), to afford 2.6 g of the target compound. 1H NMR (CDCl3): 8.92 (1H, d, J=9.3 Hz, H-arom); 8.31 (1H, d, J=9.3 Hz, H-arom); 7.82 (1H, d, J=8.8 Hz, H-arom); 7.72 (1H, d, J=8.8 Hz, H-arom); 7.57-7.68 (2H, m, H-arom); 3.94 (3H, s, OMe).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH3:12][S:13]([NH:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Br:40])=[CH:24][C:25]2[CH:30]=[N:29][C:28](SC)=[N:27][C:26]=2[N:33]=1)=[O:21])(=[O:15])=[O:14].[OH:41][CH2:42][CH2:43][S:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>ClCCl>[CH3:12][S:13]([NH:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Br:40])=[CH:24][C:25]2[CH:30]=[N:29][C:28]([NH:48][C:47]3[CH:49]=[CH:50][CH:51]=[C:45]([S:44][CH2:43][CH2:42][OH:41])[CH:46]=3)=[N:27][C:26]=2[N:33]=1)=[O:21])(=[O:14])=[O:15]
Reactant: Nc1cccc(SCCO)c1
Reactant: CSc1ncc2cc(-c3ccccc3Br)c(C(=O)NCCNS(C)(=O)=O)nc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)NCCNC(=O)c1nc2nc(Nc3cccc(SCCO)c3)ncc2cc1-c1ccccc1Br
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
2.6 g m-chloroperbenzoic acid (MCPBA, purchased from Aldrich, 57–86%) were dissolved in 20 ml dichloromethane and dried by filtration over sodium sulfate. 2 ml of this solution were added at 0–5° C. to a solution of 480 mg (0,97 mmol) of the product from example g in 3 ml dichloromethane. The mixture was allowed to reach RT and monitored by TLC. After 20 min another 0.1 ml of the above MCPBA solution were added at RT and stirring was continued for 10 min. Excess peracid was quenched by addition of 30 μl dimethylsulfide and stirring for another 20 min. The resulting mixture was used immediately without further purification for the next step: 0.625 ml of the above solution (containing 0.12 mmol) were added at RT to a solution of 22 mg meta-(2-hydroxyethylthio)aniline (0.13 mmol) in 0.5 ml dichloromethane. After 15 hrs the mixture was diluted with 10 ml dichloromethane and washed with aqueous acetic acid and with saturated potassium bicarbonate solution. Purification by chromatography on silica yielded 52 mg of the title product.
Reaction SMILES: [OH-].[K+].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[N+:17](=[CH2:19])=[N-:18].ClC(OCC)=O.[C:26]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C>C(O)C.C(OCC)C.O1CCCC1.C1(C)C=CC=CC=1>[C:26]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](=[O:36])[CH:19]=[N+:17]=[N-:18])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
The solutions of 0.4 g (7 mmol) KOH in 10 ml anhydrous ethanol and 2.14 g (10 mmol) N-methyl-N-nitroso-4-toluenesulfonamide in 30 ml diethyl ether were mixed in the reactor tube of the diazomethane distillation apparatus at 0° C. The reactor tube was kept 5 min at 0° C., and then it was placed into a 60° C. oil bath. The distillation was stopped when about 25 ml of diethyl ether containing the diazomethane was distilled over. The reaction was carried out three times for the next step. 3.14 ml (33 mmol) ethyl chloroformate was added to a solution of 6.46 g (30 mmol) BOC-L-proline and 4.60 ml (33 mmol) triethyl amine in 100 ml tetrahydrofuran at −20° C. The reaction mixture was stirred at −20° C. for 30 min. Then 75 ml diazomethane in ether (containing maximum 0.30 mmol diazomethane) was added to the reaction mixture at −20° C. The reaction mixture was stirred for 1 h at −20° C., and the flask was kept without stirring at −20° C. overnight. 120 ml toluene was added, and the organic phase was washed with saturated NaHCO3 aq and water. The organic phase was dried with anhydrous Na2SO4 and evaporated. Yield of crude product 8.3 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:28]1([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=2)=[O:33])[CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:32](=[O:33])[NH:31][CH:28]5[CH2:30][CH2:29]5)[N:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(NC1CC1)c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)NC5CC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carboxylic acid cyclopropylamide.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([NH2:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.[N:25]#[C:26]Br.C([O-])(O)=O.[Na+].C([O-])=O.[NH4+]>[Pd].O>[NH2:25][C:26]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:24]=1
Reactant: N#CBr
Reactant: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2N)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: O
Product: CCc1ccc(-n2c(N)nc3ccc(O)nc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
To 6-(benzyloxy)-N2-(4-ethylphenyl)pyridine-2,3-diamine (358 mg, 1.12 mmol) was added H2O (3.0 mL) and cyanogen bromide (178 mg, 1.68 mmol). The mixture was stirred vigorously at room temperature overnight. Saturated NaHCO3 was added and the mixture was extracted with EtOAc. After concentration in vacuo, the crude material was dissolved in MeOH (5 mL) and ammonium formate (353 mg, 5.6 mmol) was added. Pd/C (10% by wt., 100 mg) was added and the mixture was stirred in a sealed vial at 60° C. overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated. The residue was purified by preparative HPLC to give the title compound (14.4 mg) as a white solid. LCMS m/z=255.3, [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 6.54 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.5 Hz, 1H), 8.32 (broad s, 2H), 10.91 (broad s, 1H).
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C)(=O)=O.O[C:14]1([C:20]2[O:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[C:14]1([C:20]2[O:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: OC1(C2=COc3ccccc3O2)CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1=C(C2=COc3ccccc3O2)CCCC1

Procedure:
Under an inert atmosphere, 14 ml of triethylamine and 3.85 ml of mesyl chloride are added slowly to a solution of 10 ml of 2-(1-hydroxy-1-cyclohexyl)-1,4-benzodioxin in 75 ml of dichloromethane at 0° C. The mixture is brought to reflux after 15 minutes for 1.5 hours. After hydrolysis, an extraction with dichloromethane is carried out, and the organic phase is then dried over magnesium sulfate and concentrated under vacuum. The diene is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 7:3) in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:29][CH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH2:31]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COC(=O)CC1CC(N(C)C[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A solution of methyl 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)acetate (270 mg, 0.453 mmol) in methanol (8.6 mL) was treated dropwise with a solution of sodium hydroxide (36 mg, 0.91 mmol) in water (0.9 mL, 50 mmol) and the mixture was heated at 50° C. After 17 h, HPLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and treated with 0.91 mL 1.0N HCl to adjust the pH to ˜7. The solution was concentrated to remove the methanol and the resulting aqueous suspension was lyophilized to yield a white solid. The material was used as is in the next step, assuming a quantitative recovery: MS (ESI+) for C30H39N5O7 m/z 582.4 (M+H)+; MS (ESI−) for C30H39N5O7 m/z 580.4 (M−H)−; HPLC purity >95% (ret. time, 2.72 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=3[O:29][C:30]3[N:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2Oc2nccc(N)n2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): mass calcd. for C21H14FN7OS2, 399.12; m/z found, 400.2 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.22 (s, 1H), 7.79 (d, J=5.8, 1H), 7.62-7.51 (m, 2H), 7.49-7.38 (m, 3H), 7.38-7.30 (m, 3H), 7.20 (dd, J=8.0, 1.2, 1H), 7.01 (s, 2H), 6.10 (d, J=5.8, 1H).
Reaction SMILES: [C:1]1([CH:7]([NH:13]C(=O)C)[CH2:8][NH:9]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:17]>>[ClH:17].[ClH:17].[C:1]1([CH:7]([NH2:13])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)NCC(NC(C)=O)c1ccccc1
Agent: Cl
Product: NCC(N)c1ccccc1

Procedure:
A mixture of 20 g of 1-phenyl-1-acetylamino-2-acetylaminoethane and 100 ml of concentrated HCl is refluxed for 15 hours. The product separates on chilling and is filtered off, washed with acetone and then with ether to yield 13.7 g of the title C compound. This material is stored in the refrigerator (on standing at room temperature, this material will lose part of the bound HCl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[N:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: COC(=O)c1cccnc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccnc1-c1cccc(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 4.02 g (20 mmole) of 3-bromophenyl boronic acid, 6.86 g (40 mmole) of methyl 2-chloronicotinate, 600 mg of tetrakis-(triphenylphosphine) palladium, 25 mL of 2M solution of sodium carbonate, 50 mL of toluene, and 13 mL of ethanol was heated 20 hours at 80°. The reaction mixture was cooled to r.t. and partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was washed with sodium chloride solution several times, and dried over anhydrous magnesium sulfate. Solvent removal gave a crude product, which was chromatographed on silica gel using 1:4 ethyl acetate:hexane mixture as eluant to give methyl 2-[3-bromophenyl]nicotinate as white amorphous powder.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[C:8]=2[C:26]2[CH:31]=[CH:30][C:29](OC)=[CH:28][C:27]=2[CH:34]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:43][OH:44]>CCO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]3[O:22][CH2:23][CH2:24][O:25]3)[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:34]=[N:43][OH:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3C=O)n(CC3OCCO3)c2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=NO)n(CC3OCCO3)c2c1
Yield: 95 %

Procedure:
To a solution of methyl methyl 3-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-2-(2-formylphenyl)-1H-indole-6-carboxylate (prepared in analogous fashion to Example 4, Step 2, using 2-formylphenylboronic acid) in EtOH (0.05 M), were added aqueous solutions of sodium carbonate (2M; 1.3 eq) followed by hydroxylamine hydrochloride (2M; 1.3 eq). The reaction was stirred at RT for 2 h, before the EtOH was reduced in vacuo and the residue partitioned between EtOAc and water. The aqueous fraction was extracted a second time with EtOAc and the combined organics washed with water and then brine before being dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (95%); MS (ES+) m/z 463 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:3]1=[O:17].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([C:23](N2C3C=CC=CC=3OC2=S)=[O:24])=[CH:21][CH:20]=1>CN1CCCC1=O>[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([NH:16][CH:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]2=[O:17])[C:13]([OH:15])=[O:14])=[O:24])=[CH:21][CH:20]=1
Reactant: CN1C(=O)C(CC(N)C(=O)O)c2ccccc21
Reactant: O=C(c1ccc(Cl)cc1)n1c(=S)oc2ccccc21
Solvent: CN1CCCC1=O
Product: CN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 Grams of 3-(1-methyloxindol-3-yl)-2-aminopropionic acid prepared in Reference Example 5 was suspended in 50 ml of 1-methyl-2-pyrrolidone, then 2.2 g of 3-(4-chlorobenzoyl)benzoxazolin-2-thione was added thereto, and the reaction mixture was stirred at a room temperature for 3 days. The reaction mixture was poured into an ice-water, and the crystals formed were collected by filtration, then the crystals were dissolved in 1N-sodium hydroxide aqueous solution, then the resulting solution was acidified by using 10%-hydrochloric acid, and the crystals formed were collected by filtration. The crystals were dried, washed with chloroform, there was obtained 1.1 g of 2-(4-chlorobenzoylamino)-3-(1-methyloxindol-3-yl)propionic acid. White powdery substance. Melting point: 115°-120° C.
Reaction SMILES: C([O:8][CH:9]([CH2:18][CH2:19][F:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])C1C=CC=CC=1>CO.[Pd]>[F:20][CH2:19][CH2:18][CH:9]([OH:8])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1CC(CCF)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1CC(O)CCF
Reaction time: 5 h

Procedure:
To a solution of 1-(2-(benzyloxy)-4-fluorobutyl)-2-methylbenzene (3.0 g, 11.03 mmol) in MeOH (50 ml) was added 10% Pd/C (0.3 g) under nitrogen and stirred at 40 psi for 5 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation method E. (Yield 1.5 g).
Reaction SMILES: [Cl:1][C:2]12[C:15]([Cl:17])([Cl:16])[C:5]([Cl:18])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[C:8]([Cl:13])[C:7]3=[O:14])[C:4]([Cl:19])=[C:3]2[Cl:20].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:15]([Cl:16])([Cl:17])[C:5]([Cl:18])([C:6]3[C:7]([OH:14])=[C:8]([Cl:13])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:19])=[C:3]2[Cl:20]
Reactant: O=C1C=C(Cl)C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Oc1cc(Cl)c(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of 256 grams (0.62 mol.) of 1,2,3,4,6,9,9-heptachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 24, and 500 ml. of methanol in a 2 liter reaction flask was stirred at room temperature while air in the reaction vessel was swept out with nitrogen. Six ml. of pyridine was then added to the liquid-solid mixture. The resulting reaction mixture was continuously stirred, and refluxed vigorously for 8.5 hours. After cooling the mixture to 0° C., it was filtered, and the crude solid was washed with cold Skellysolve. Yield 121 grams. The product was recrystallized from a mixture of 1000 ml. of Skellysolve and 250 ml. of acetone. M.P. 120.5°-122° C. The product has the following structure: ##STR57##
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:9][CH:10]=1)[CH2:3][OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:12]([NH:11][C:8]1[N:9]=[CH:10][C:5]([C@@H:2]([OH:1])[CH2:3][O:4][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc([C@@H](O)CO)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
A slurry of (R)-N-(5-(1,2-dihydroxy-ethyl)-pyridin-2-yl)-acetamide (71.2 g, 362 mmol) in anhydrous pyridine (362 ml) was cooled to 5° C. and treated with p-toluenesulfonyl chloride (69.18 g, 362 mmol) in one portion. The reaction mixture was stirred at 5° C. for 20 minutes, then the cooling bath was removed and the mixture was stirred at ambient temperature for two hours. The mixture was then concentrated, dissolved in 30 ml of methanol, concentrated and dissolved in toluene (300 ml) and concentrated again. The residue was treated again with methanol and toluene, then the residue was dissolved in ethyl acetate and washed sequentially with half-saturated brine, brine and dried over sodium sulfate. The filtrate was evaporated to afford 102.2 g (80%) of the title product as light buff crystals. Recrystallization from ethanol-cyclohexane afforded the title product as colorless crystals. mp 124-126° C. 1H NMR (dmso-d6): δ=10.5 (br, 1 H); 8.21 (d, 1 H); 7.94 (d, 1 H); 7.68 (d, 2 H); 7.51 (d of d, 1 H); 7.41 (d, 1 H); 5.87 (d, 1 H); 4.76 (d of d, 1 H); 4.05 (d, 2 H); 2.41 (s, 3 H); 2.10 (s, 3 H). MS (Cl): m/z=351 (M+H+). Optical Rotation: −36.181° (c=1.19, acetone). Analysis: Calculated for C16H18N2O5S: C, 54.85%; H, 5.18%; N, 7.99%. Found: C, 54.91%; H, 5.34%; N, 8.06%.