Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:17][CH3:18])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.Cl>[OH-].[Na+]>[CH3:18][S:17][C:7]1[NH:8][C:9]2[C:14]([C:15](=[O:16])[C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCOC(=O)c1c(SC)nc2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1[nH]c2ccccc2c(=O)c1C(=O)O
Yield: 85 %

Procedure:
4-Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g, 30 mmol) was heated under reflux in NaOH solution (10%, 100 mL) for 1.5 h. After cooling, the mixture was acidified with concentrated HCl to pH 4. The resulting solid was collected via filtration, washed with water (100 mL) and MeOH (100 mL) to give 2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-16) as a white solid (6 g, 85%). 1H NMR (CDCl3) δ 16.4 (br s, 1 H), 11.1 (br s, 1 H), 8.19 (d, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.84 (t, J=8, 8 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 2.74 (s, 3H); ESI-MS 235.9 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1)=[O:20].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.ClCCl>[CH3:34][C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[NH:16][C:7]2[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:17]=[C:5]3[N:6]=2)=[CH:26][CH:25]=1)([CH3:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: COC(=O)CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nc(C)cc3n2)cc1
Reaction time: 72 h
Yield: 15.2 %

Procedure:
In a 50 ml pear flask was added 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 200 mg, 0.89 mmol) in pyridine (5 ml) to give a light yellow solution. A solution of methyl 3-(4-(chlorocarbonyl)phenyl)-3-methylbutanoate (230 mg, 0.89 mmol) in dichloromethane (1 ml) was added to the reaction mixture at room temperature, which was then stirred for 72 h. Saturated NaHCO3 was added and pyridine was mostly removed in vacuo. The residue was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 30-40% ethyl acetate/hexanes) to give the titled product (60 mg, 15% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 8.61 (s, 2H), 8.10-8.15 (m, 8H), 7.87-7.92 (m, 5H), 7.54-7.59 (m, 8H), 7.50-7.54 (m, 5H), 6.28 (s, 2H), 3.54 (s, 8H), 2.68-2.71 (m, 5H), 2.50 (s, 8H), 1.49 (s, 6H); ESI-MS: m/z 443.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[N:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])=[O:3].C(OC(C)C)(C)C>[Pd].C(O)C.C1COCC1>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([S:2]([CH3:1])(=[N:4][C:5](=[O:10])[C:6]([F:9])([F:7])[F:8])=[O:3])=[CH:16][CH:15]=1
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc(N)cc1
Reaction time: 0.75 h
Yield: 89 %

Procedure:
292 mg palladium on charcoal (10%/50% moisture) was added to a solution of 1.34 g (4.52 mmol) (RS)-S-methyl-S-(4-nitrophenyl)-N (trifluoroacetyl)sulfoximide in 45 ml ethanol and 8 ml THF and was hydrogenated for 45 minutes under normal pressure at 24° C. The mixture was filtered and concentrated by evaporation. The residue obtained was stirred with diisopropyl ether. The solid was filtered off with suction and dried. 1.07 g (4.03 mmol; yield: 89%) of the product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To the solution of 2-chloro-3-nitrobenzoic acid (1 g, 4.96 mmol), DMF (0.02 ml, 0.258 mmol) in DCM (20 mL) at 0° C. was added dropwise oxalyl chloride (0.478 ml, 5.46 mmol). The reaction was warmed to rt after the addition. After 3 h, methanol (10 mL) was added dropwise to the reaction mixture and the reaction was stirred at rt for 18 h and then the reaction was concentrated. The residue was dissolved in dichloromethane and passed through a plug of silica gel eluting with a 50% ethyl acetate/n-hexanes mixture. The filtrate was concentrated in vacuo to give the title compound as a white solid (1 g, 93% yield). MS (ESI) m/z: 216.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#N.[CH3:12]I.[H-].[Na+].C[N:17]([CH3:20])C=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([C:20]#[N:17])([CH3:12])[CH3:6]
Reactant: CI
Reactant: CN(C)C=O
Reactant: COc1ccccc1CC#N
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1C(C)(C)C#N
Yield: 85 %

Procedure:
By a method analogous to that of Example 3(a), o-methoxybenzyl cyanide was methylated with methyl iodide and sodium hydride in dimethylformamide to give the desired compound in 85% yield.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 89 %

Procedure:
224 mg Of octene-1, 329 mg of triethoxysilane and 400 mg of toluene were placed in a glass reaction tube and 0.004 ml of acetic acid was then added to the tube. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of the octene-1 was 96% and n-octyltriethoxysilane was produced at a yield of 89%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(Cc3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 3 h

Procedure:
To 3-(3-nitro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1402, 141 mg, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 21 mg, 0.512 mmol) under an atmosphere of nitrogen. After thirty minutes, p-toluenesulfonyl chloride (114 mg, 0.60 mmol) in N,N-dimethyl-formamide was added and the reaction was stirred for three hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. All solids were filtered and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give the compound (552, 120 mg, 58%). MS(ESI)[M+H+]+=485.25.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](I)=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[N:28][CH:29]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)nc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
A mixture of 4-(diphenylamino)phenylboronic acid (7.00 g, 24.2 mmol), 5-bromo-2-iodopyridine (7.56 g, 26.6 mmol), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 1.21 mmol), Na2CO3 (9.18 g, 86.6 mmol), H2O (84 mL) and tetrahydrofuran (THF) (140 mL) was degassed with argon for about 1.5 h. while stirring. The stirring reaction mixture was then maintained under argon at 80° C. for about 19 h. Upon confirming consumption of the starting material by thin layer chromatography (TLC) (SiO2, 19:1 hexanes-EtOAc), the reaction was cooled to RT and poured over EtOAc (500 mL). The organics were then washed with saturated sodium bicarbonate (NaHCO3, H2O) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified via flash chromatography (SiO2, 2:1 hexanes-dichloromethane) to afford Compound 23 (9.54 g, 98% yield) as a light yellow, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[Br:9]Br.O>C(O)(=O)C>[Br:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Oc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-hydroxypyridine (100 g) and bromine (40.1 mL) in acetic acid (400 mL) was stirred at r.t. for 1 h. The mixture was poured into 3 L of water and stirred for 30 min then filtered. The residual solid was washed with 2 L of cold water, air dried and then coevaporated with toluene three times and with benzene two times. The white solid (81 g) so obtained was used in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.[F:23][C:24]([F:36])([F:35])[C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.ClC1C=CC=CC=1C1N=NC(NNC(=O)CC2C=CC(C(F)(F)F)=CC=2)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH:15][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[N:30][C:25]([C:24]([F:23])([F:36])[F:35])=[CH:26][CH:27]=2)=[N:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Agent: O=C(Cc1ccc(C(F)(F)F)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Yield: 103.1 %

Procedure:
The title compound (40 mg, 100%) as a white solid was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (25 mg, 0.075 mmol) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (23 mg, 0.113 mmol) in a manner analogous to that in which N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide (Example 11A) was prepared. HPLC/MS: retention time=3.53 min, [M+H]+=517.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-:23])=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-tert-butylquinoline (400 mg, 2.16 mmol, Journal of the Indian Chemical Society, 1998, 823) and mCPBA (639 mg, 2.59 mmol) in chloroform (10 ml) was stirred for 2 hours at room temperature. The mixture was concentrated and the crude residue was applied to a silica gel (NH silica) column and eluted with DCM/MeOH (20:1) to furnish the title compound (433 mg, quant.) as pale orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:35])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.[Cl:52][C:53]1[N:54]=[N:55][C:56](Cl)=[CH:57][CH:58]=1>>[Cl:52][C:53]1[N:54]=[N:55][C:56]([C:40]2[CH:41]=[CH:42][C:37]([CH2:36][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:25])(=[O:26])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:22](=[O:35])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:38][CH:39]=2)=[CH:57][CH:58]=1
Reactant: CC1(C)OB(c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)N(COCC[Si](C)(C)C)S4(=O)=O)cc3)cc2)OC1(C)C
Reactant: Clc1ccc(Cl)nn1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)cc2)S1(=O)=O

Procedure:
5-(4-{4-(2,4-Dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (385 mg, 0.5 mmol) was treated as described in general procedure G using 3,6-dichloropyridazine (149 mg, 1 mmol) to give 5-{4-[2-[4-(6-chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [H-].[Na+].[O:3]([C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:4].[CH3:15]I>CN(C=O)C>[CH3:15][N:9]1[C:10]2[C:6](=[C:5]([O:3][CH3:4])[CH:13]=[CH:12][C:11]=2[Br:14])[CH:7]=[CH:8]1
Reactant: CI
Reactant: COc1ccc(Br)c2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1ccn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60%, 0.23 g, 5.75 mmol) in DMF (18 mL) was added a solution of 4-methoxyl-7-bromoindole (1.1 g, 4.87 mmol) in DMF (2 mL). After 1 h at room temperature, the mixture was treated with methyl iodide (0.45 mL, 7.23 mmol) with cooling in an ice-water bath. The reaction mixture was allowed to warm up room temperature and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate and the extract washed with water and brine, and dried (sodium sulfate). Evaporation of solvent gave a crude product, which was used without further purification. 1H NMR (400 MHz, CDCl3) 3.92(σ,3H), 4.13 (s, 3H), 6.35 (d, J=8.21 Hz, 1H), 6.55 (d, J=3.13 Hz, 1H), 6.89 (d, J=3.52 Hz, 1H), 7.22 (d, J=8.21 Hz, 1H).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:45])([CH2:43][CH3:44])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[CH2:18][C:17]([F:20])([F:19])[CH2:16][N:15]1C(OC(C)(C)C)=O)=O>C(OCC)(=O)C.O>[CH3:45][C:7]([CH3:6])([CH2:43][CH3:44])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=4)=[CH:31][CH:30]=3)[CH2:18][C:17]([F:20])([F:19])[CH2:16][NH:15]2)[NH:11][CH:10]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CC(F)(F)CN2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (947 mg, 12.3 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (138 mg, 0.25 mmol) in xylenes (10 mL). After stirring in a sealed tube at 160° C. for 1 h, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was dissolved in trifluoroacetic acid (1 mL). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to afford the title compound. (M+H) found: 443.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.[CH2:22]([O:26][CH:27]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:24][CH3:25]>>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][CH:27]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:39][CH:38]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Reactant: CCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Product: CCCCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OCC
Yield: 54.2 %

Procedure:
The title compound (0.25 g, 53%) was prepared as a colorless liquid from 2-(phenoxazin-10-yl)ethyl methanesulfonate (0.3 g, 0.98 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoate (0.26 g, 0.97 mmol) obtained in preparation 6 by an analogous procedure to that described in example 6 (Method B).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25]C=CC=2)[CH:23]=[CH:22][CH:21]=1.CC1C=C(O)C=C([OH:37])C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:24]([CH3:25])[CH:23]=[C:22]([OH:37])[CH:21]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of ethyl 7-bromo-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (EXAMPLE 1C) (0.9 g), 5-methylbenzene-1,3-diol (1.028 g), triphenylphosphine (0.868 g), dibenzylazodicarboxylate (0.762 g) and tetrahydrofuran (40 ml) was stirred at room temperature for 19 hours. After removal of the solvent, the crude product was purified by flash chromatography silica gel, (Analogix, SF65-200 g) eluting with 0-10% ethyl acetate in hexane.
Reaction SMILES: CO[C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=1)=[O:4].[NH2:17][C:18]([NH2:20])=[NH:19]>CN1C(=O)CCC1.O>[CH3:10][C:9]1[C:5]([C:3]([NH:19][C:18]([NH2:20])=[NH:17])=[O:4])=[CH:6][N:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=1
Reactant: COC(=O)c1cn(-c2ncccn2)cc1C
Reactant: N=C(N)N
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2ncccn2)cc1C(=O)NC(=N)N
Temperature: 25 °C
Yield: 53.4 %

Procedure:
250 mg 4-methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carboxylic acid methyl ester was dissolved in 0.3 mL of NMP. After addition of 1 g guanidine (preparation according to known literature) the mixture was heated under argon for 1 h to 90° C. Completion of the reaction was checked by LCMS. The mixture was cooled to room temperature and then diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water (twice), dried over anhydrous sodium sulfate. After filtration the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column flash chromatography (eluent: dichloromethane/methanol=5/1) to obtain 150 mg of N-(4-methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carbonyl)-guanidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-n2ccc3ccccc32)cc1
Reaction time: 16 h
Yield: 70.3 %

Procedure:
A slurry of 2.63 g (22.5 mmol) indole, 5.26 g (22.5 mmol) 4-iodoanisole, 0.43 g (3 mmol) CuBr and 4.14 g (30 mmol) K2CO3 in 60 ml anhydrous N-methylpyrrolidinone (NMP) was heated to reflux with stirring for 16 hr. The solution was allowed to cool and then poured into water and shaken with ethyl acetate. The entire biphasic system was filtered through a pad of Celite, the phases were separated, and the organic phase was dried over MgSO4 and concentrated. The crude product was chromatographed on silica (5-7% EtOAc-Hexane) to afford 3.53 g 1-(4-methoxyphenyl)-1H-indole as a colorless solid.
Reaction SMILES: C(O)C.[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([O:18]CC)=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5].[OH-].[Na+]>O>[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)c1cccc2c1CCCC2C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1CCCc2c(C(=O)O)cccc21
Temperature: 50 °C

Procedure:
In 90 ml. of ethanol is dissolved 9.6 g. of ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate and a solution of 2.5 g. of sodium hydroxide in 90 ml. of water is added. The mixture is stirred under heating at 50°C for 3 hours, after which the ethanol is distilled off. Then, following the addition of 2N hydrochloric acid, the residue is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the crystalline residue is recrystallized from benzene. The described procedure gives 1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid, melting point: 177°-179°C.