Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:20])[N:10]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][CH:24]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=[C:9]3[NH:8][CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:21])[CH2:3][CH2:4]2)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:25][CH:24]=1
Reactant: Cc1nc(NC2CCC(F)(F)CC2)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(NC2CCC(F)(F)CC2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 23.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-difluorocyclohexyl)-2-methylquinazoline-4,8-diamine (Intermediate-53, 100 mg, 0.342 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 147 mg, 0.513 mmol), oxalyl chloride (97 mg, 0.77 mmol), DMF (1 drop) and DIPEA (132 mg, 1.026 mmol) in CH2Cl2 (3 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.18-8.15 (t, J=5.8 Hz, 1H), 8.06-8.04 (d, J=8.4 Hz, 1H), 7.97-7.95 (d, J=7.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.38-7.36 (d, J=8.0 Hz, 1H), 4.44 (m, 1H), 4.30 (d, J=5.6 Hz, 2H), 2.46 (s, 3H), 2.10-1.99 (m, 6H), 1.76-1.73 (m, 2H), 1.14 (s, 9H); MS (m/z): 562.32 (M+H)+.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[C:32]1([Mg]Br)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:40]1([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)=[O:9])[C:41]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc4ccccc34)sc2c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone (1.58 g, 3.6 mmol) (see U.S. Pat. No. 5,420,349) in tetrahydrofuran (THF, 12 mL) was cooled to 0° C. and treated with a 0.65M THF solution of 1-naphthylmagnesium bromide (20.0 mL, 13 mmol) (prepared from 1-bromonaphthalene, catalytic iodine, and magnesium turnings in THF). The mixture was allowed to warm to ambient temperature and when the starting material was consumed, the reaction was quenched with water and extracted with ethyl acetate (a small amount of methanol was added to improve solubility). The organic layer was washed with water (2×), and brine (2×), dried (sodium sulfate), and concentrated. The residue was purified via chromatography (silica gel, 0-10% methanol in methylene chloride) to provide 1.08 g (58%) of the title compound as a yellow foam: 1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H), 1.60 (m, 4H), 2.47 (m, 4H), 2.68 (t, J=5.9 Hz, 2H), 3.92 (s, 3H), 3.96 (t, J=5.9 Hz, 2H), 6.47 (d, J=8.8 Hz, 2H), 7.06 (dd, J=2.3 Hz, 8.9 Hz, 1H), 7.27-7.50 (m, 5H), 7.54 (d, J=8.8 Hz, 2H), 7.67-7.75 (m, 2H), 7.79 (d, J=8.9 Hz, 1H), 8.06-8.09 (m, 1H); MS (FD) m/e 521 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[ClH:9].[C:10]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])[NH:11][NH2:12]>C(O)C>[ClH:9].[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[N:12][NH:11][C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: NNC(=O)Oc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C(NN=Cc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 6.43 gm (0.06 mole) of 4-pyridinecarboxaldehyde, 11.31 gm (0.06 mole) of phenyl carbazate hydrochloride and 300 ml of 95% ethanol is refluxed 4 hr. The reaction mixture is evaporated to dryness. The crude product is suspended in 200 ml of boiling absolute ethanol and sufficient methanol added to give a solution. The hot solution is filtered, the filtrate cooled to room temperature and then chilled in the freezer. The crystals are collected, washed with Skellysolve B and dried to yield 11.0 gm (66%) of the title compound having a melting point of 224.4° C. (decomp).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C@H:7]([NH:16][C:17]2[C:18](=[O:30])[N:19]([CH2:24][C:25]([O:27]CC)=[O:26])[C:20]([Cl:23])=[CH:21][N:22]=2)[CH2:6]1)(=[O:4])=[O:3].[OH-].[Na+].Cl>CCO>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C@H:7]([NH:16][C:17]2[C:18](=[O:30])[N:19]([CH2:24][C:25]([OH:27])=[O:26])[C:20]([Cl:23])=[CH:21][N:22]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(S(C)(=O)=O)C[C@H]2c2ccccn2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)N1C[C@@H](Nc2ncc(Cl)n(CC(=O)O)c2=O)[C@H](c2ccccn2)C1

Procedure:
A solution of 3-(1-methylsulfonyl-trans-4-(2-pyridyl)-pyrrolidin-3-ylamino)-6-chloro-1-ethoxycarbonylmethylpyrazinone from step 11 above (0.20 g, 0.47 mmol) and aqueous NaOH (0.18 mL of a 4.0 N solution, 0.71 mmol) in EtOH (7 mL) was stirred at ambient temperature for 2 h. Aqueous HCl (0.12 mL of a 6.0 N solution, 0.72 mmol) was added, and the solvents were removed in vacuo to give the title compound as an amorphous solid containing NaCl (0.2 g, HPLC RT=3.99 min, method A).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]O>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: COc1cccc(COC(=O)c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)c1
Reaction time: 5 h

Procedure:
A mixture of 3.6 g (10 mmol) of tert.butyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 1.7 g (7.2 mmol) of tetraethyl orthotitanate and 20 ml of 3-methoxybenzyl alcohol is stirred at 120° for 5 hours, a small amount of solvent being removed in vacuo three times during this time. The excess 3-methoxybenzyl alcohol is subsequently distilled off in a high vacuum, the residue is taken up in 30 ml of chloroform, the chloroform solution is treated with 25 ml of water, stirred for 1.25 hours and filtered through siliceous earth. The organic phase is separated, the aqueous phase is extracted once with chloroform, the combined chloroform extracts are dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate/n-hexane there is obtained m-methoxybenzyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][ 1,4]benzodiazepine-1-carboxylate of melting point 126°-127°.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH3:32])[C:8](=[O:31])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]2)=[N:11][CH:10]=1.[N-:42]=[N+:43]=[N-:44].[Na+].[Cl-].C([NH+](CC)CC)C.Cl>CN1CCCC1=O>[F:41][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=1)[CH2:6][N:7]([CH3:32])[C:8](=[O:31])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[NH:44][N:43]=[N:42][N:30]=3)[CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1-c1cc(N2CCN(CC#N)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-c1cc(N2CCN(Cc3nnn[nH]3)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
A mixture of 0.10 g (0.17 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide (Example 55), 34 mg (0.52 mmol) sodium azide and 36 mg (0.26 mmol) triethylammonium chloride in 1 ml 1-methyl-2-pyrrolidone was heated at reflux for 2 h. After cooling to room temperature 6 ml ice water were added. The mixture was acidified with 1N hydrochloric acid solution to pH 1-2 and extracted with dichloromethane. Drying of the combined extracts with sodium sulfate, concentration and flash column chromatography afforded 95 mg (88%) of the title compound as a light brown solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]([C:15]1([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][C:35]3[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=3)[CH:25]=2)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14].[CH3:43]O.P([O-])(O)(O)=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:11][O:12][C:13]([C:15]1([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][C:35]3[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=3)[CH:25]=2)[CH2:20][CH2:19][C:18](=[CH2:43])[CH2:17][CH2:16]1)=[O:14]
Reactant: CO
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Product: C=C1CCC(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (4.88 g, 13.7 mmol) was suspended in THF. Potassium bis(trimethylsilyl)amide (13.6 mmol, solution in toluene) was added slowly and the mixture was stirred at room temperature for 1 h. The mixture was cooled in a acetone/dry ice bath and the compound of step 1 of example 55 (3.00 g, 6.83 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Methanol and an aqueous sodium dihydrogenphosphate solution were added. The mixture was extracted with diethyl ether, the combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (1.40 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC#N>C1COCC1>[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH:37][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-Trifluoromethyl-benzoylamino)acetic acid (4.2 g, 17 mmol) and NMM (2.8 mL, 25.5 mmol) in dry THF (30 mL) at −10 to −15° C. under N2, was slowly added isobutylchloroforinate (2.4 mL, 17.85 mmol) via syringe. The reaction mixture gradually became pink. 15 min later, a solution of (3R)-1-benzylpyrrolidin-3-amine (3.0 g, 17 mmol) in THF (15 mL) was dropwise added to the above mixed anhydride over 20 min, maintaining reaction temperature <−10° C. The reaction mixture became a dark red color. 1 h later, the reaction mixture was allowed to warm to rt, and quenched with water (25 mL), extracted with EtOAc×3, dried, filtered and concentrated to give an orange solid. MeCN was added and concentrated to remove EtOAc. Then MeCN (15-20 mL) was added to afford a slurry, which was chilled in ice bath and stirred for 30 min. After filtration, the solid product was rinsed with cold MeCN (10-15 mL) until the filtrate was colorless After dried under high vacuum overnight, a pale yellow solid product: 5.0 g (73%) was afforded. MS (M+H+)=406.2; 1H NMR (CDCl3) δ 8.16 (s, 1 H), 8.00 (dd, 1H), 7.78 (dd, 1H), 7.57 (m, 1H), 7.25 (m, 6H), 7.06 (m, 1H), 6.39 (m, 1H), 4.48 (m, 1H), 4.04 (d, 2H), 3.62 (d, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.57 (m, 1H), 2.36 (m, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:6]=1.[H][H]>CO.[Ni]>[NH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:8]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:21])=[O:20]
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CON(C)C(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reaction time: 5 h
Yield: 45.2 %

Procedure:
N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide (4.2 g) was dissolved in methanol (120 ml), and Raney nickel (approx. 700 mg) was added. With a hydrogen balloon attached, hydrogenation was effected on a magnetic stirrer. After 5 h, the catalyst was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by means of preparative chromatography. The product-containing fractions were combined, freed of the acetonitrile, basified with sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.73 g of the desired compound were obtained.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(-c3ccncc3)ccc21
Temperature: 100 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
To a solution of 1-acetyl-5-bromoindoline (12.01 g) and 4-pyridinylboronic acid (9.22 g) in 1,2-dimethoxyethane (500 mL) were added [1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.23 g) and potassium phosphate (31.9 g) at ambient temperature and the mixture was stirred at 100° C. for 20 hours. The mixture was evaporated in vacuo to remove 1,2-dimethoxyethane and the residue was dissolved in a mixture of ethyl acetate (600 mL) and water (300 mL). The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 1-acetyl-5-(4-pyridinyl)indoline (4.42 g) as a white powder.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:21])[N:11]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[NH:12][CH:13]=2)[CH:6]=[N:7][CH:8]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[ClH:1].[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:11]2[C:10](=[O:21])[C:9]([C:5]3[CH:4]=[C:3]([C:22]#[N:23])[CH:8]=[N:7][CH:6]=3)=[CH:13][NH:12]2)[CH:19]=1
Reactant: CN(C)C=O
Reactant: Cc1ccnc(-n2[nH]cc(-c3cncc(Br)c3)c2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Product: Cc1ccnc(-n2[nH]cc(-c3cncc(C#N)c3)c2=O)c1
Temperature: 25 °C

Procedure:
200 mg (0.5 mmol) of the compound from Example 7, 47 mg (0.4 mmol) of zinc cyanide and 19 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) are reacted in 3 ml of DMF at 220° C. in a single-mode microwave oven (Emrys Optimizer) for 50 min. The reaction mixture is then concentrated under reduced pressure, the residue is taken up in 2 ml of ethanol and the mixture is adjusted with 1 N aqueous sodium hydroxide solution to pH 10. The mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated under reduced pressure and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with 0.1% formic acid added to the water). The product-containing fractions are concentrated under reduced pressure, the residue is dissolved in 1 ml of ethanol and 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added. The mixture is stirred at RT for min and then concentrated under reduced pressure, and the residue is dried under high vacuum.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]1([CH2:30][C:31]([OH:33])=[O:32])[CH2:29][CH2:28][CH2:27]1.C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]2([CH2:30][C:31]([OH:33])=[O:32])[CH2:29][CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC1(CC(=O)O)CCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1nc(C(=O)NC2(CC(=O)O)CCC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 92.9 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (45 mg, 0.14 mmol) and (1-amino-cyclobutyl)-acetic acid (91 mg, 0.70 mmol) (APAC Pharmaceuticals LLC, Columbia Md.) in DMA (2 mL) was added NaOMe solid (38 mg, 0.70 mmol). The resultant mixture was heated in a 150° C. oil bath for 3 h. Reaction mixture was diluted with water and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 54 mg (0.13 mmol) in 92% yield. LC-MS ESI−: 416.17 (M−1)−.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1.Cl[C:32]([O:34][CH3:35])=[O:33].Cl>ClCCl>[C:17]([C:3]1[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:6]([C:2]=1[NH:1][C:32]([O:34][CH3:35])=[O:33])=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c(Cl)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)OC)c2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-amino-2-benzoyl-6-chloro-1H-indole-1-caboxylate (step 2, 1.5 g, 4.4 mmol) and pyridine (0.50 ml, 6.6 mmol) in dichloromethane (20 ml) was added methyl chloroformate (0.40 ml, 5.3 mmol) at room temperature. After stirring for 3 h, the mixture was poured into 2N aqueous HCl (20 ml) and extracted with dichloromethane (30 ml×2). The combined organic layers were dried (MgSO4) and concentrated to give 1.7 g (quant.) of the title compound as yellow amorphous solids.
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:32])[C:7]1[C:8](=[C:12](Cl)[C:13]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]=1Cl)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:1]([N:5]=[C:6]([OH:32])[C:7]1[C:8](=[C:12]([S:42][C:39]2[CH:40]=[CH:41][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[C:13]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]=1[S:42][C:39]1[CH:40]=[CH:41][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C(O)c1c(Cl)c(Sc2ccccc2)c(Sc2ccccc2)c(Cl)c1C(=O)O
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN=C(O)c1c(Sc2ccc([N+](=O)[O-])cc2)c(Sc2ccccc2)c(Sc2ccccc2)c(Sc2ccc([N+](=O)[O-])cc2)c1C(=O)O

Procedure:
2 g (4.09 millimols) of 4,5-bis-(phenylthio)-3,6-dichlorophthalic acid N-n-butylimide, 1.46 g (9.41 millimoles) of p-nitrothiophenol, 2.55 g (18.45 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 50° C. for 20 hours. The mixture is cooled, acidified and extracted with methylene chloride. After recrystallisation from tetrahydrofuran, 1.9 g (78% of theory) of the title compound are obtained; melting point 175°-7° C.
Reaction SMILES: [F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.[OH:14]OS([O-])=O.[K+]>CO.O>[F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:9][C:8]([S:10]([CH3:11])=[O:14])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(F)c(F)cc2s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1nc2cc(F)c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 240 mg (1.1 mmol) 5,6-difluoro-2-methylsulfanyl-benzothiazole in 8 mL methanol under nitrogen at 0-5° C., was added drop wise a solution of 1.019 g (1.658 mmol) oxone in 4 mL water. The reaction mixture was stirred at 0° C. for 1 h. The suspension was diluted with water (10 mL). The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered, concentrated in vacuo and purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 130 mg (50.6%) of the title compound as white solid. MS(m/e): 234.1 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:12]1)=O)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[C:28]1([C:20]2[NH:21][C:22]3[C:27]([C:19]=2[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(c1c(-c2ccccc2)[nH]c2ccccc12)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: O=C(c1c(-c2ccccc2)[nH]c2ccccc12)C1CCCNC1
Yield: 93.2 %

Procedure:
A solution of 11.6 g (26.5 mmol) of 3-(2-phenyl-1H-indol-3-ylcarbonyl)piperidine-1-carboxylic acid benzyl ester and 6.4 g (79.5 mmol) of 1,4-cyclohexadiene in ethanol under an atmosphere of nitrogen was charged with 1 g of 10% palladium on carbon. The mixture was heated under reflux for 2 hr, after which it was cooled and filtered to remove the catalyst, and the filtrate evaporated in vacuo to afford 7.5 g (24.7 mmol; 93%) of (2-phenyl-1H-indol-3-yl)piperidin-3-ylmethanone as a clear oil. δH (360 MHz; CDCl3) 1.02-1.15 (1H, m, aliphatic), 1.51-1.70 (2H, m, aliphatics), 1.73-1.84 (2H, m, aliphatics), 2.51-2.62 (1H, m, aliphatic), 2.78-2.89 (3H, m, aliphatics), 2.92-3.02 (1H, m, aliphatic), 7.22-7.28 (2H, m, aromatics), 7.36-7.47 (3H, m, aromatics), 7.50-7.56 (2H, m, aromatics), 8.21-8.27 (1H, m, aromatic), 10.46 (1H, br s, NH); m/z (ES+) 305 (M++H, 100%).