Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17](O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH3+:57])[CH3:56])=[CH:51][CH:50]=1)=[O:48].CCN(C(C)C)C(C)C>C(#N)C>[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH:57][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[O:18])[CH3:56])=[CH:51][CH:50]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c21
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(tert-butoxycarbonyl)indoline-7-carboxylic acid (0.5 g, 1.9 mmol), HATU (795 mg, 2.09 mmol) and (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride (511 mg, 2.85 mmol) were added to acetonitrile (12.7 ml). The solution was cooled in an ice bath and DIPEA (993 ul, 5.7 mmol) was added. The ice bath was removed and the mixture stirred for 2 hours at RT. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 8.40 (d, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.30 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 5.10 (m, 1H), 4.00 (m, 2H), 3.85 (s, 3H), 3.05 (m, 2H), 1.45 (d, 3H), 1.40 (s, 9H).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=O)[C:4]([OH:6])=[O:5].[CH3:14][C:15]1[C:22]([C:23](=[S:25])[NH2:24])=[C:18]2[S:19][CH:20]=[CH:21][N:17]2[N:16]=1>CCO>[CH3:14][C:15]1[C:22]([C:23]2[S:25][C:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:24]=2)=[C:18]2[S:19][CH:20]=[CH:21][N:17]2[N:16]=1
Reactant: O=C(O)C(=O)C(Br)c1ccccc1
Reactant: Cc1nn2ccsc2c1C(N)=S
Solvent: CCO
Product: Cc1nn2ccsc2c1-c1nc(C(=O)O)c(-c2ccccc2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of 3-bromo-2-oxo-3-phenylpropanoic acid (197 mg, 1.00 mmol) and 6-methylpyrazolo[5,1-b][1,3]thiazole-7-carbothioamide (267 mg, 1.10 mmol) in EtOH (10 ml) was stirred at 50° C. for 1 h. The reaction mixture was allowed to cool to rt, the resulting precipitate was collected by filtration and then washed with EtOAc to obtain title compound (328 mg, 96%) as a colorless solid. 1H-NMR (DMSO-d6) δ 2.61 (3H, s), 7.43-7.59 (6H, m) 8.31 (1H, d, J=4.2 Hz), 12.99 (1H, br s).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]([CH3:62])[CH3:61])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]([CH3:62])[CH3:61])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (10 mg) and triethylamine (6 μL) are dissolved in dichloromethane (1 mL), treated with isopropyl chloroformate (28 μL, 1 M solution in toluene) and stirred for 12 hours at room temperature. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is used directly in the next step. LC (method 5): tR=1.27 min.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1COCC1>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(OC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Yield: 93.9 %

Procedure:
To a solution of methyl mandelate (0.83 g) and triethylamine (0.51 g) in THF (40 ml) was added 4-chlorophenyl isocyanate (0.77 g). The reaction mixture was mixed at 60° C. for 3 hours, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate/hexane=1/6 to 1/3) to obtain the title compound as a pale brown crystal (1.5 g, 91%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[C:11]([CH:22]=1)=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[O:13][N:14]=2.[I:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=1.O>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[O:13][N:14]=[C:10]3[CH:9]=[CH:8][C:7]([C:28]([C:27]4[CH:34]=[CH:35][C:24]([I:23])=[CH:25][CH:26]=4)=[O:29])=[CH:22][C:11]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(I)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
BuLi 1.6M (0.106 mol) was added dropwise at −70° C. to a solution of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.0816 mol), obtained in Example A1a, in THF (250 ml) under N2 flow. The mixture was stirred at −70° C. for 15 min. A solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.098 mol) in THF (150 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour then brought to room temperature. The mixture was hydrolysed with water, extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (48 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 16.5 g (44%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-iodophenyl)-methanone, mp.196° C. (intermediate 35).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=1>>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[C:17]([CH3:16])[CH:18]=1)[CH:25]=[CH2:26]
Reactant: C=CCOc1cccc(C)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOc1ccc(C=O)c(C)c1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 81 %

Procedure:
N-methyl formanilide 19.4 ml (158 mmole), was chilled to 13° C., where it began to solidify. Phosphorus oxychloride, 13.7 ml (147 mmole), was added with stirring, under nitrogen. After 25 minutes, the temperature was 45° C. and the reaction had again begun to solidify. The compound of Step A, 14 g (95 mmole), was added and the mixture was stirred and heated in a 70° C. oil bath. The reaction exothermed to 95° C. Stirring was continued under nitrogen for 30 minutes. The bath was removed and when the temperature reached 35°, the mixture was dissolved in chloroform. Ice was added and the layers were separated and washed once with water, twice with saturated sodium bicarbonate, once again with water and once with brine. The organic layer was chromatographed on 450 ml silica, eluting with chloroform to give 13.54 g (81%) of subtitled product which was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17](O)=[O:18])[N:14]=[CH:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[OH:10][CH2:9][CH2:8][N:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:17]([C:15]1[N:14]=[CH:13][N:12]([CH3:11])[CH:16]=1)=[O:18]
Reactant: OCCNC1CCOCC1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cnc(C(=O)N(CCO)C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A mixture of 2-(tetrahydro-2H-pyran-4-ylamino)ethanol (3.45 g), 1-methyl-1H-imidazole-4-carboxylic acid (3.00 g), HATU (13.6 g), diisopropylethylamine (12.4 mL) and acetonitrile (52 mL) was stirred at room temperature for 2 hours. The solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=98:2 to 96:4) to give the titled compound (2.34 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:4][N:3]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(I)cnc(N)c34)cc2)c1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(C#CCCO)cnc(N)c34)cc2)c1
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A suspension of Example 144A (0.227 g, 0.45 mmol) in piperidine (3 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with 3-butyn-1-ol (0.069 mL, 0.91 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and CuI (5 mg, 0.023 mmol), then heated to 80° C. in a sealed tube for 30 minutes. The resulting homogeneous solution was cooled to room temperature and concentrated under a stream of nitrogen. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 164 mg (81%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.65 (t, J=6.78 Hz, 2H), 3.63 (q, J=6.73 Hz, 2H), 4.92 (t, J=5.59 Hz, 1H), 5.70 (s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.28 (m, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.49 (s, 1H), 7.60 (d, J=8.48 Hz, 2H), 7.93 (s, 1H), 8.65 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 443 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[C:21]([F:20])([F:30])[F:31])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13])=[N+:2]=[N-:3].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:15]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:21][C:22]([O:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:23])[C:8](=[O:12])[C:7]1=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN1CCNC(=O)C1=O
Reactant: O=C(C=Cc1cccnc1)OC(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCN1CCN(C(CC(=O)OC(c2ccccc2)c2ccccc2)c2cccnc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
A mixture of 0.5 g of 1-(2-azidoethyl)-2,3-dioxopiperazine, 1.72 g of diphenylmethyl 3-(3-pyridyl)-acrylate, 0.2 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene and 2.5 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, after which 30 ml of ethyl acetate and 20 ml of water were added to the resulting residue and the pH was adjusted to 6 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layer was washed with 20 ml of water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol=20:1) to obtain 0.71 g of diphenylmethyl 3-[4-(2-azidoethyl)-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as a light-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC1(C)N([O])C(C)(C)CCC1.CC(OC)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: OCc1nc2ncc(Br)cn2n1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=Cc1nc2ncc(Br)cn2n1
Yield: 74.2 %

Procedure:
A slurry of (6-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (6.5 g, 28.51 mmol) from step 1 above in dichloromethane (60 mL) was added PhI(OAc)2 (10.1 mg, 31.4 mmol) and with catalytic TEMPO (334 mg, 2.14 mmol). After reaction at room temperature for 3 hours, the reaction is complete. MTBE is added slowly (50 mL) to crystallize the product, filtration followed by drying the product by vacuum oven overnight. The filtrate was concentrated and purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light white solid (combine total 4.8 g, 75% yield). 1H NMR (300 MHz, CDCl3) □ ppm 8.96 (d, J=2.45 Hz, 1H) 9.09 (d, J=2.45 Hz, 1H) 10.22 (s, 1H). MS: (APCI) 228 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12](=[O:14])[C:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:10]([OH:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:37][CH2:38]Cl)[CH:34]([CH3:36])[CH3:35]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12](=[O:14])[C:11]([C:15]3[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[C:10]([O:24][CH2:38][O:37][CH2:33][CH:34]([CH3:36])[CH3:35])[C:9]=2[CH3:25])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(-c2c(O)c(C)c(-c3ccc(Cl)cc3)oc2=O)c(C)c1
Reactant: CC(C)COCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2c(OCOCC(C)C)c(C)c(-c3ccc(Cl)cc3)oc2=O)c(C)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
7.1 g (20 mmol) of 6-(4-chlorophenyl)-4-hydroxy-5-methyl-3-(2,4,6-trimethyl-phenyl)-2-pyrone in 50 ml of ethyl acetate are introduced in the absence of moisture. 2.02 g (20 mmol) of triethylamine are added thereto at 20° C. and a solution of 2.4 g (20 mmol) of i-butoxychloromethane in 20 ml of ethyl acetate is added dropwise at 0° C. with cooling. The mixture is then further stirred for 20 h at 20° C. and the reaction is followed by thin-layer chromatography. The solution is filtered off from the precipitated triethylamine hydrochloride using suction and washed with ethyl acetate. The combined mother liquors are washed twice, each time with 50 ml of half-saturated common salt solution, dried over magnesium sulfate and evaporated in vacuo. 8.8 g of crude product are obtained. 5.6 g (63% of theory) of 6-(4-chlorophenyl)-4-[(2-methyl-1-propoxy)-methoxy]-5-methyl-3-(2,4,6-trimethylphenyl)-2-pyrone are obtained as an oil by flash chromatography on 500 g of silica gel 60 (35-70 μm) using toluene:acetone 50:1 as mobile phase.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:40][C:24]3=[CH:25][N:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:30]=4[F:39])[CH:28]=[C:23]3[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[F:39][C:30]1[CH:31]=[C:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=[CH:34][C:29]=1[C:27]1[CH:28]=[C:23]2[CH:22]=[C:21]([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[O:40][C:24]2=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1.2 mL) is added to 4-[5-(2-fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.78 g) in dichloromethane (14 mL). The mixture is stirred at room temperature overnight. Aqueous NaHCO3 solution is added, the resulting mixture is stirred for 5 min, and the phases are separated. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water and dried (Na2SO4). The solvent is evaporated to give the title compound. LC (method 1): tR=0.59 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][NH:26]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[C:20]([Br:19])[CH:28]=3)[CH2:24][CH2:25]2)=[O:17])[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccc2c(c1)NCC2
Reactant: C[C@@H]1CN(CC(=O)O)CCN1C(=O)OC(C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
(R)-4-Carboxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol), 6-bromo indoline (100 mg, 0.43 mmol) and triethylamine (0.148 mL, 1.06 mmol) were dissolved in DCM (1.94 mL) at ambient temperature. PyBrop (199 mg, 0.43 mmol) was added and the reaction stirred for 18 h. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give the title compound (97 mg, 52%) as a pale yellow oil. 1H NMR (Me-d3-OD): 8.32 (1H, s), 7.24-7.10 (2H, m), 5.50 (1H, s), 4.38-4.17 (3H, m), 3.83 (1H, d), 3.31 (1H, s), 3.17 (2H, t), 2.91 (1H, d), 2.81 (1H, d), 2.33 (1H, dd), 2.20-2.09 (1H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:20]([O:22]C)=O)=[CH:9][CH:8]=[C:7]1[OH:24])=O.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:20]([C:10]1[C:11]2[C:6](=[N:5][C:4]3[C:13]([N:12]=2)=[C:14]([OH:19])[C:15]([CH3:18])=[C:16]([OH:17])[C:3]=3[CH:1]=[N:30][CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[C:7]([OH:24])=[CH:8][CH:9]=1)=[O:22]
Reactant: CN(C)CCCN
Reactant: COC(=O)c1ccc(O)c2nc3c(C=O)c(O)c(C)c(O)c3nc12
Product: Cc1c(O)c(C=NCCCN(C)C)c2nc3c(O)ccc(C(=O)NCCCN(C)C)c3nc2c1O
Reaction time: 0.08 h

Procedure:
6-Formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylic acid, methyl ester (1.107 g, 3.27 mmol), was stirred with 50 g of 3-(dimethylamino)propyl amine (Aldrich Chemical Company, Milwaukee, Wis., USA) at 60° C. for 1.5 hours. The reaction mixture was then cooled in an ice bath for 20 minutes and the crude imine amide product precipitated from solution. The precipitated solid was collected by filtration and washed with 50 ml of acetonitrile. The retention time for this product, employing the HPLC system and method described in Example 3 above, was 4.6 minutes.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:26][O-:27].[Na+].ClCCl>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([O:27][CH3:26])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[O-]
Reactant: Clc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A heterogeneous mixture containing 3-(4-(1H-imidazol-1-yl)benzyl)-2,4-dichloro-6-iodoquinoline (1.2 g, 2.5 mmol, Intermediate 17: step b) and sodium methoxide (1.6 g, 30 mmol) in toluene (25 mL) was heated to 110° C. After 2 hours, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added and the mixture was filtered through Celite®, rinsing the filter cake with dichloromethane. The filtrate was concentrated to provide the title compound as an off-white solid. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methylacetophenone (2.02 mL, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 191-193° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 2.39 (s, 3H), 3.41 (m, 1H), 6.84 (s, 1H), 6.92 (m, 1H), 7.10 (m, 2H), 7.27 (m, 1H), 7.37 (m, 2H), 7.75 (d, 2H).