Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH3:11][C:12](C)([O-])[CH3:13].[K+].[I-].[K+].C(Br)C=C>C1COCC1>[CH2:13]([CH:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH:12]=[CH2:11]
Reactant: CC(C)(C)[O-]
Reactant: OCCOCCOCCO
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(O)COCCOCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Allyl-triethylene glycol was prepared according to the literature method with modifications (Setz O, et al. Angew Chem Int Ed Engl. 1995, 34, 803-805). Thus, the mixture of triethylene glycol (11.83 g, 78.8 mmol), potassium t-butoxide (4.42 g, 39.4 mmol) and potassium iodide (0.65 g, 3.94 mmol) in THF (500 mL) was stirred at room temperature for 0.5 h, into which was added dropwise allyl bromide (4.767 g, 39.4 mmol) in THF (120 mL) over a period of 1.5 h. After continuing to be stirred at room temperature for 36 h, the mixture was filtered through a celite pad. The crude product, obtained after removal of solvents under vacuum, was purified by a silica gel column chromatography eluting with hexane/ethyl acetate (1:1) to afford the product (4.9 g, 25.8 mmol, 65% yield) with chemical structure confirmed by 1H NMR and MS.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:7]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:35]3[CH2:34][CH2:33][N:32]([S:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([Cl:18])[CH:20]=5)[CH:25]=4)(=[O:31])=[O:30])[CH2:37][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)[N:7]=1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)c[nH]1

Procedure:
In a similar manner to Example 4 except for the use of 4-(2-aminoimidazol-4-yl)benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:15]([C:16](O)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:19]([OH:21])=[O:20])[NH:3]1.N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[CH2:16]=[C:15]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:19]([OH:21])=[O:20])[NH:3][C:2]1=[O:1]
Reactant: O=C(O)C1CCCCCCCCCCC(C(=O)O)C(=O)N1
Agent: C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C1CCCCCCCCCCC(C(=O)O)NC1=O
Temperature: 65 °C

Procedure:
2-oxo-1-azacyclotetradecane-3,14-dicarboxylic acid (0.868 g, 2.9 mmol) is dissolved in pyridine (15.0 mL). Piperidine (0.060 mL, 0.59 mmol) is added, followed by paraformaldehyde (0.133 g, 4.43 mmol), and the reaction is heated to 65° C. for 4 hours. The reaction is then cooled to 0° C., and concentrated hydrochloric acid is added to bring the pH to approximately 2. The reaction is partitioned between ethyl acetate and water, and the aqueous phase is extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated to give 3-methylidene-2-oxo-1-azacyclotetradecane-14-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:24]=[O:25])C.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([CH:24]=[O:25])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a stirred solution 5-(4-chlorophenyl)thiophene-2-carboxylic acid (11 g, 0.046 mol) in dry THF (150 ml) was added n-BuLi (63 ml, 0.102 mol, 1.6 M solution in hexane) in a dropwise manner at −78° C. under inert atmosphere. The temperature was slowly raised to 0° C. over a period of 4 h. The reaction mixture was again cooled to −70° C. and dry DMF (34 ml, 0.43 mol) was added slowly. After completion of the addition of DMF, temperature was raised to −10° C. and stirred for 2 h. The reaction mixture was again cooled to −30° C. and 1.5 N HCl (50 ml) was added slowly and reaction was allowed to come to RT. The reaction mixture was extracted with EtOAc (4×200 ml). The combined organic layer washed with water (2×150 ml), brine (2×150 ml), dried (Na2SO4) and concentrated. The crude product washed with p-ether (100 ml) to afford 8 g of the title compound (65%). Rf=0.2 (CHCl3:MeOH, 8:2). This was found pure enough to carry further. Since this intermediate is unstable it has to be used immediately in the next step.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=[CH:13][CH:12]=4)[NH:9][C:10]=31)[CH2:4][CH2:3]2.I[CH3:26]>CN(C)C=O>[CH3:26][N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc4ccccc34)c(=O)c12
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1cccc3ccccc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 34.6 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 46; 150 mg, 0.47 mmol) and iodomethane (118 μL, 1.88 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 40 g column, eluting with 70-90% ethyl acetate/hexanes to give (4S,7R)-1,7,8,8-tetramethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (54 mg, 35%) as a white solid. ES(+)-MS (M+H) 333.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:15]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:17]([CH3:19])[CH:18]=1)=[O:4].[OH-].[Li+]>>[CH3:13][S:10]([C@H:8]1[CH2:7][N:6]([C:14]2[N:15]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=[C:17]([CH3:19])[CH:18]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(C)(=O)=O)C[C@H]2C(=O)O)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-methanesulfonyl-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=378.0 [M+H]+.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.NN>>[CH2:3]([N:10]1[C:3]([NH2:10])=[CH:4][C:5]([CH3:6])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCc1ccccc1
Agent: Cl
Agent: NN
Product: Cc1cc(N)n(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Synthesized using the procedure for 22 except benzyl hydrazine dihydrochloride was used as the hydrazine. After the reaction mixture was stopped and cooled to room temperature, solid precipitated which was filtered off and dried in vacuum oven to provide the title compound (3.6 g, 98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.40-7.34 (m, 2H), 7.34-7.27 (m, 3H), 5.57 (s, 1H), 5.35 (s, 2H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 151.48, 146.65, 135.16, 129.19, 128.61, 128.00, 91.19, 49.13, 11.44.
Reaction SMILES: [CH:1]1([O:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[N:15]2[N:16]=[C:17](F)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1>>[Br:10][C:11]1[N:15]2[N:16]=[C:17]([NH:9][CH2:8][CH2:7][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: NCCOC1CCCC1
Product: Brc1cnc2ccc(NCCOC3CCCC3)nn12
Yield: 69 %

Procedure:
The 2-(cyclopentyloxy)ethanamine was reacted with 3-bromo-6-fluoroimidazo[1,2-b]pyridazine, using the amine displacement conditions described in example 5.6.42, part A to afford 69% product.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[C:4]2[C:5]([N:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8](=[O:9])[C:3]=12)=[O:6].O>CO.[BH4-].[K+]>[F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[C:4]2[C:3]=1[CH:8]([OH:9])[N:7]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]2=[O:6]
Reactant: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1O
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
4,7-Difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 6.41 g of 3,6-difluoro-N-isobutylphthalimide in 70 cm3 of methanol and 1.44 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 3 hours and is then cooled to a temperature in the region of 0° C. and 45 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 30° C., followed by addition of 80 cm3 of dichloromethane. After separation of the phases by settling, the aqueous phase is extracted twice with 80 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 5.68 g of 4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a yellow solid melting at 129.5° C. (Rf=0.48, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([Cl:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:22][C:11]1[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=[C:15]2[C:10]=1[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2c(Cl)cc(C#N)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(Cl)cc(C#N)cc21
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-(3-bromo-phenyl)-8-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (374.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(8-chloro-6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (118.8 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 396.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[NH2:16][C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH:26]([CH3:37])[CH2:25]2)=[C:19]([CH3:38])[CH:18]=1.Cl>CC(O)C>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([NH:16][C:17]2[CH:18]=[C:19]([CH3:38])[C:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH:26]([CH3:37])[CH2:25]3)=[CH:21][C:22]=2[F:23])=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: Cc1cc(N)c(F)cc1C1CCN(C(=O)OC(C)(C)C)C(C)C1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNC(C)C4)cc3F)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (346 mg, 1.42 mmol) and tert-butyl 4-(4-amino-5-fluoro-2-methylphenyl)-2-methylpiperidine-1-carboxylate (352 mg, 1.09 mmol) in 2-propanol (10 mL) was treated with cone. HCl (12N, 0.43 mL). The mixture was sealed and heated in a microwave at 130° C. for 45 min. The mixture was concentrated. The residue was purified by RP-HPLC to afford 5-Chloro-N2-(2-fluoro-5-methyl-4-(2-methylpiperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 430.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22][OH:23].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1C[O:38][CH2:37]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:21](=[O:24])[CH2:22][O:23][C:37]1=[O:38]
Reactant: C1CCOC1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2NC(=O)CO)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)COC2=O)C1
Reaction time: 8 h

Procedure:
N-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-2-hydroxy-acetamide (20 mg) was dissolved in absolute THF (2 ml), and reacted at room temperature with sodium hexamethyldisilazide solution (0.5 ml; 2 M in THF) with stirring. Afterward, 1,1-carbonyldiimidazole (13 mg) was added and the mixture was stirred at room temperature for 2 h. After standing overnight, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water and basified with sodium hydrogencarbonate solution, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in water/acetonitrile and the clear solution was freeze-dried overnight. 10 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH2:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCn1cc(-n2c(C)c(Sc3cncc(C(=O)OC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 5-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])=[O:13]>CO.[Pd].C>[F:11][C:4]1[C:5]([F:10])=[C:6]([F:9])[C:7]([F:8])=[CH:2][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])=[O:13]
Reactant: COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2Br)cc1O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2cc(F)c(F)c(F)c2F)cc1O
Reaction time: 4 h

Procedure:
The title compound was prepared via catalytic hydrogenation of the compound prepared in Example F above. Briefly, the starting material was in methanol and placed in a closed vessel. A catalytic amount of 10% Pd/charcoal was added and the mixture was hydrogenated at 60 psi H2 for 4 h. The resulting mixture was filtered through celite, the solvent was evaporated and the residue was purified by chromatography (silica; EtOAc/Hexane, 1:4) to yield the title compound. 1H-NMR (CDCl3): δ 7.43 (1H, m), 6.80 (1H, br s), 6.73-6.60 (3H, m), 5.67 (1H, s), 3.84 (3H, s). MS(EI): 351 (20, M+), 138 (100). Anal. Calcd. for C13H9F4NO4S: C, 44.45; H, 2.58; N, 3.99; S, 9.13. Found: C, 44.39; H, 2.59; N, 3.94; S, 9.24.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:3][CH2:6][CH:7]([CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CO)CCCCOc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(CCl)CCCCOc1ccccc1

Procedure:
A solution of 60 g of thionyl chloride in 50 ml of CHCl3 was added dropwise to 100 g of 1-Hydroxy-2-methyl-6-phenoxy-hexane in 200 ml of CHCl3 and 0.5 ml of DMF. The solution was refluxed until the development of the gas was finished and then poured onto ice. The aqueous phase was extracted twice with CHCl3 and the combined organic phases were washed with water and finally with a saturated NaHCO3 -solution, dried with MgSO4, evaporated and the residue was distilled off.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24])([OH:16])=[O:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:24][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:14]([OH:16])=[O:15])=[O:25])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccccc1C(=O)O
Product: O=C(O)c1ccccc1C(=O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 8 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.64 g of 2'-carboxyacetophenone. Yield 0.36 g (11%), m.p. 178°-180° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: CC(C)(C)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (76 mg, 89%), MS (ISN) m/z=344.5 [(M+H)+], mp 300° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][OH:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([O:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: OCC1CN(c2ccccc2)CCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 20 h

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinemethanol (7.8 g, 27.6 mmol) in dimethylformamide under nitrogen and add 60% sodium hydride (1.22 g, 30.4 mmol). Stir for 20 h as solid slowly dissolves. Add 1-fluoro-4-nitrobenzene (4.29 g, 30.4 mmol) and stir at room temperature. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction, add water (100 mL) to the reaction mixture and extract with methylene chloride (2×100 mL). Remove the solvent in vacuo and recrystallize the residue from ethyl acetate/hexanes (1/1) (80 mL) to provide the title compound.
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>O1CCOCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=[CH:12][C:3]=1[CH:2]=[O:1]
Reactant: Cc1cnc2ccccc2n1
Reactant: O
Solvent: C1COCCO1
Product: O=Cc1cnc2ccccc2n1

Procedure:
To a solution of SeO2 (2.3 g, 20.9 mmol) and water (1 mL) in 1,4-dioxane (25 mL) at reflux was added 2-methylquinoxaline (2 g, 13.9 mmol) in 1,4-dioxane (4 mL). After refluxing for 4 h, the reaction mixture was filtered. The filtrate was concentrated and purified by column chromatography to give 500 mg of the desired product. LC-MS: m/z 159 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N+:21]([C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:29]([C:27]2[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:30])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Agent: Cl
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])s1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 5-nitrothiophene-2-carboxylic acid. MS (m/e): 428.3 (MH−, 100%).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])(=[O:13])=[O:12])[C:5]=2[O:4][C:3]1=[O:21].[OH-:22].[K+]>CO>[OH:4][C:5]1[C:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])(=[O:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:2]([CH3:1])[C:3]([OH:21])=[O:22]
Reactant: CC1C(=O)Oc2c1cccc2S(=O)(=O)c1ccccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(S(=O)(=O)c2ccccc2Cl)c1O

Procedure:
3-Methyl-7-(2-chlorobenzenesulfonyl)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(2-chlorobenzenesulfonyl)phenyl]propionic acid, mp. 180°-181° C.