Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=1)C.[CH3:38][C:39]([C:41]1[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][C:46]=1[OH:47])=[O:40]>O1CCCC1>[CH2:30]([O:29][C:17]1[CH:16]=[C:15]([C:14](=[O:13])[CH2:38][C:39]([C:41]2[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][C:46]=2[OH:47])=[O:40])[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(O)cc1O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (200.8 mL, 240 mmol), 2,4-dihydroxy acetophenone, 14 (9.12 g, 60 mmol) in tetrahydrofuran (150 mL) and ethyl-3,4-dibenzyloxy benzoate, 9 (21.7 g, 60 mmol) in tetrahydrofuran (100 mL) were reacted to afford 17, 1-(3,4-bis-benzyloxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (55 g), which was then cyclized with Dowex-H+ (12 g) in 2-propanol (400 mL) in a similar way as described for 22 to afford 23 (Frederique, A. A. A.; Hageman, J. A.; Guido, R. M. M. H.; Van Der Vijgh, W. J. F.; Bast, A.; Menge, W. M. P. B. J. Med. Chem. 2000, 43, 3752.). Yield 24 g (89%); mp 245-247° C. (lit. 244-245° C.); MS (FAB) 451 (M++1); IR (KBr) 3426, 1607; 1H NMR (200 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.51-7.30 (m, 10H), 7.18 (d, J=8.5 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.83 (s, 1H), 5.26 (s, 2H), 5.21 (s, 2H).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([NH2:35])[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>>[C:25]1([NH:35][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: Nc1cccc2c1CCCC2
Product: CCCCCCCCCCCc1noc(-c2cccc(CNc3cccc4c3CCCC4)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 460.4. HPLC (Condition A), Rt: 6.32 min (HPLC purity: 68.9%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]2[C:7]([C:9]([OH:26])=[C:10]([C@@H:13]3[CH2:18][CH2:17][C@@H:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:11](=[O:12])[C:3]=2[CH:2]=1)=[O:8].C1(=O)C2C=CC=CC=2C(=O)CO1.ClC1C=CC(C2CCC(C=O)CC2)=CC=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:16]2[CH2:15][CH2:14][CH:13](/[CH:10]=[C:9]3\[O:26][C:11](=[O:12])[C:3]4[CH:2]=[CH:1][CH:6]=[CH:5][C:4]=4[C:7]\3=[O:8])[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: O=C1COC(=O)c2ccccc21
Agent: O=CC1CCC(c2ccc(Cl)cc2)CC1
Product: O=C1O/C(=C\C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
The present invention provides a new process for the preparation of atovaquone, which process comprises reacting 1H-2-benzopyran-1,4(3H)-dione (compound of formula (III)) with 4-(4-chlorophenyl)cyclohexanecarbaldehyde (compound of formula (IV)) to produce the novel intermediate (3Z)-3-{[4-(4-chlorophenyl)cyclohexyl]methylidene}-1H-2-benzopyran-1,4(3H)-dione (compound of formula (II)) which then undergoes internal rearrangement to produce atovaquone (compound of formula (I)).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:31])[CH2:25][C:26](OCC)=[O:27])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH2:1]([C:3]1[C:4]([NH:23][CH:24]([CH3:31])[CH2:25][CH2:26][OH:27])=[N:5][C:6]([CH2:21][CH3:22])=[C:7]([C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(C)Nc1nc(CC)c(-c2cc3c(cc2OC)CCCC3)nc1CC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1NC(C)CCO
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A 250 mL dry round bottom flask equipped with a magnetic stir bar was charged with a solution of ethyl 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butanoate (Example 38, 2.82 g, 6.62 mmol), in THF (37.6 mL) and cooled with an ice bath. A solution of 1M LAH in THF (33.11 mL, 33.11 mmol) was added to the reaction mixture dropwise. Strong effervescence was observed. The reaction was stirred at ° C. for an additional 15 minutes after the addition was complete, then the ice bath was removed and the reaction stirred at ambient temperature for 2 hours. The reaction color changed from pale yellow to brown. The reaction was cooled with an ice bath again, and quenched with ethyl acetate (33 mL) followed by the dropwsie addition of a saturated aqueous solution of KHSO4 (6.62 mL). Effervescence was observed again. After stirring at ° C. for 20 minutes the ice bath was removed. The addition of KHSO4 caused a gel to form, which turned into a solid within 30 minutes. MgSO4 was added to the mixture, and the heterogeneous solution was filtered through MgSO4. After rinsing with ethyl acetate, the filtrated was concentrated to give 2.74 grams of an auburn oil. This material was purified by Biotage MPLC (120 g column, 5% acetone in toluene) to give 2.16 grams (85%) of 3-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}butan-1-ol as a white foam. Rf 0.20 (40% ethyl acetate in heptane). IR (diffuse reflectance) 2965, 2931, 2875, 2859, 2835, 1572, 1493, 1463, 1445, 1391, 1309, 1248, 1232, 1205, 1171 cm−1. OAMS supporting ions at: ESI+ 384.2. HRMS (ESI) calcd for C23H33N3O2+H1 384.2651. found 384.2667. HRMS (ESI) calcd for C23H33N3O2+H1 384.2651. found 384.2667.
Reaction SMILES: C(N[C:10]([N:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O>[CH2:21]([N:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18](=[O:19])[NH:20][C:10]1=[S:11])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCN(C(=S)NC(=O)c1ccccc1)c1nc[nH]c1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Yield: 94 %

Procedure:
A mixture of 4-[[(benzoylamino)carbonothioyl](pentyl)amino]-1H-imidazole-5-carboxamide (11.8 g, 0.0263 mol) and 1 M of sodium hydroxide in water (75 mL) was heated to reflux for 3 h. Solid was formed in the reaction mixture. The reaction mixture was adjusted to pH 3-4 with concentrated HCl with cooling in an ice bath. The solid was filtered, washed with water and air-dried to give the product (9.0 g, 65% purity, 94% yield). The product was used for the next step without further purification. LCMS calculated for C10H15N4OS (M+H): 239.1. found: 239.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]=[N+:15]=[N-:16])[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3.O.[C:31](OC=C)(=O)[CH3:32]>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:32]=[CH:31][N:16]=[N:15]3)[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reactant: C=COC(C)=O
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Yield: 47 %

Procedure:
5.0 g (12.39 mmol) of 2-[2-fluoro-4-[(5R)-5-(azidomethyl)-2-oxo-3-oxazolidinyl]phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 9 of the preparation example 1 was dissolved in 100 ml of vinyl acetate, and the solution was heated to reflux for 30 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 2.5 g (47%) of 2-[2-fluoro-4-[(5R)-5-(1,2,3-triazol-1-ylmethyl)-2-oxo-3-oxazolidinyl]phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH2:5]2.[CH3:32][N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:26]1([CH2:25][C@H:12]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:37]4[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=4)[CH:3]=3)[C:7]2=[O:11])[CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Br)ccc2C1=O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](CC1CCCCC1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 28.9 %

Procedure:
A mixture of 2-[(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (103.5 mg, 0.2151 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47 mg, 0.23 mmol), N,N-diisopropylethylamine (0.11 mL, 0.63 mmol), and bis(tri-t-butylphosphine)palladium (0.011 g, 0.021 mmol) in 1,4-dioxane (4 mL, 50 mmol) and water (0.2 mL, 10 mmol) was stirred at 110° C. for 40 min under microwave irradiation. Direct purification on prep.—HPLC afforded 30 mg (29% yield) of the desired intermediate. LC-MS found: 483.1 (M+H)+.
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([Cl:21])[CH:15]=1)(=[O:13])[NH2:12]>>[C:11]([C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)=[C:16]([Cl:21])[CH:15]=1)(=[O:13])[NH2:12]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: OC1CNCc2ccoc21
Product: NC(=O)c1ccc(OC2CNCc3ccoc32)c(Cl)c1

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([OH:17])=[C:10]2[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1Cc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzylpiperazin-2-one (0.29 g, 1.54 mmol) and diethyl ethoxymethylenemalonate (0.35 g, 1.63 mmol) in toluene was heated in a sealed tube at 80° C. for 4 hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (10 mL), cooled to 0° C. under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 2.0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the title compound.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][CH2:7][O+](CC)CC.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>ClCCl>[CH2:6]([O:23][C:19](=[N:18][C:17]1[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=1)[CH:20]([CH3:22])[CH3:21])[CH3:7]
Reactant: CC[O+](CC)CC
Reactant: CC(C)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=Nc1cccc(C(F)(F)F)c1)C(C)C

Procedure:
Add a solution of 5.0 g. (0.03 moles) of triethyloxonium fluoborate in 13 ml. of dichloromethane to a solution of 7.3 g. (0.03 moles) of 3'-trifluoromethylisobutyranilide in 60 ml. of dichloromethane and reflux for 20 hours. Remove 50 ml. of dichloromethane and add 150 ml. of dry ether to precipitate out the product of this example as its fluoborate salt, m.p.=95°-100°C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[N:24]([CH3:25])[N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:29]([N:31](CC)CC)C.[ClH:36].CN.C(OP(C#N)(=O)OCC)C>O.CN(C=O)C>[ClH:36].[CH3:29][NH:31][C:26]([C:22]1[CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:6]3[C:3]4[CH:4]=[CH:5][S:1][C:2]=4[CH:9]=[CH:8][CH:7]=3)[CH2:11][CH2:12]2)[N:24]([CH3:25])[N:23]=1)=[O:28]
Reactant: CCN(CC)CC
Reactant: Cn1nc(C(=O)O)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
A DMF solution of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid (0.3 g, 0.75 mmol) was cooled on ice and triethylamine (0.73 ml, 5.2 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol) and diethylphosphorocyanidate (DEPC)(0.25 ml, 1.4 mmol) were added thereto, and then, the mixture was stirred at room temperature for 24 hours. To the reaction solution, triethylamine (0.73 ml, 5.2 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol) and DEPC (0.25 ml, 1.4 mmol) were added and the mixture was stirred at room temperature for 4 days. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extracted material was washed with water and dried over magnesium sulfate. The solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1-+ethyl acetate). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and a solution of 4N-hydrochloric acid/ethyl acetate was added thereto. The insoluble matter precipitated was obtained by filtration and dried to obtain N-methyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxamide hydrochloride (0.24 g) as white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:8]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:17]([O:16][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([CH:3]=[O:2])[NH:6]2)=[CH:11][C:10]=1[O:14][CH3:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc2cc(OC)c(OCc3ccccc3)cc2[nH]1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cc(C=O)[nH]c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution of the ester (56) (1.0 g, 3.22 mmol) prepared as described in example 248 in tetrabydrofuran (10 mL) was added a suspension of lithium aluminum hydride (0.150 g, 3.86 mmol) in tetrahydrofuran (10 mL) dropwise, the reaction mixture was stirred at room temperature for 20 min. Water (1 mL) was added dropwise and then dilute sodium hydroxide (1 mL) was added, the solution was stirred for 10 min and then filtered through Celite and concentrated. The resulting yellow oil was dissolved in chloroform (20 mL) and then manganese dioxide (2.2 g, 26.0 mmol) was added, the reaction mixture was heated at 50° C. for 1 h and then filtered through Celite and concentrated. The residue was recrystallized from dichloromethane to give 6-(benzyloxy)-5-methoxy-1H-indole-2-carbaldehyde (57) (0.74 g, 82%) as pale yellow needles. Found: C, 72.53; H, 5.42; N, 4.92. C17H15NO3 requires: C, 72.58; H, 5.37; N, 4.98.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[C:9]=1Br.N#N.C([Sn](CCCC)(CCCC)[C:60]([O:62][CH2:63][CH3:64])=[CH2:61])CCC>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.O1CCOCC1>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[C:9]=1[C:60]([O:62][CH2:63][CH3:64])=[CH2:61]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(NC(=O)C1(C)COC(C)(C)OC1)c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C(C)NC(=O)C2(C)COC(C)(C)OC2)nc2c(-c3cnc4ccc(F)cc4c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Yield: 83.2 %

Procedure:
N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (63.7 mg, 0.078 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.0 mg, 0.0078 mmol) were combined in a microwave tube, and the cap was crimped on. The headspace was purged with dry N2 (×2), and tributyl[1-(ethyloxy)ethenyl]stannane (53 μL, 0.16 mmol) and 1,4-dioxane (0.69 mL) were added. The suspension was sparged with dry N2 for ca. 3 min. The tube was lowered into a pre-heated 100° C. oil bath and stirred over night. The dark reaction mixture was then cooled, partitioned between aq. KF (2 mL, 0.5 M) and ether (ca. 3 mL). The layers were separated, and the aqueous was extracted with ether (1×3 mL), the organics were combined, washed with brine (2 mL), dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude matrial (105 mg) was adsorbed into silica gel, and purified by flash chromatography (15 g silica, hexanes to 25% EtOAc in hexanes, the 5% MeOH in DCM). Like fractions were combined, and concentrated to give N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-(1-ethoxyvinyl)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (52.5 mg, 83%) as a yellow film. The material contained a small amount of triphenylphosphine oxide, and carried on as is.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][S:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:20])=[CH:15][CH:16]=2)[N:11]([CH3:21])[CH:10]=1)=O>N1C=CC=CC=1>[Cl:5][CH:6]([Cl:3])[S:7][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:20])=[CH:15][CH:16]=2)[N:11]([CH3:21])[CH:10]=1
Reactant: Cn1cc(S(=O)CCl)c(=O)c2ccc(F)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cc(SC(Cl)Cl)c(=O)c2ccc(F)cc21
Reaction time: 0.02 h

Procedure:
To an efficiently stirred and gently cooled 4.2 ml mixture of thionyl chloride (“SOCl2”) and 1.05 ml of pyridine (“Py”) at −3° C. was added 1.015 g (3.708 mmol) of 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (monochloroflosequinan) (Compound 1 of FIG. 1). This addition was made in multiple alloquots over a period of approximately 1 min. During this addition, cooling was applied to keep the temperature in the range 0-5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.[CH3:17]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH:12]([CH3:17])[CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cc(C(N)=S)c(Br)cn1

Procedure:
The title compound was synthesized by a method analogous to the synthesis of Intermediate 42 starting with Intermediate 46 and Lawesson's reagent in THF.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:64]([NH:66][C@H:67]([CH2:71][OH:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:54][S:55][CH2:56][C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)=[O:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:80]>C(O)(C(F)(F)F)=O.O.C(OCC)C>[NH2:1][C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:64]([NH:66][C@H:67]([CH2:71][OH:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:54][S:55][CH2:56][C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)=[O:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:80]
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@@H](N)Cc2ccccc2)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Reaction time: 0.5 h

Procedure:
13 g BOC-Phe-(D)Trp-Lys(Z)-Thr-Cys(MBzl)-Thr-ol are dissolved in 60 ml cold TFA/H2O (15:1) and the solution allowed to stand for 30 min. at room temperature. The reaction mixture is stirred into a mixture comprising 3 liters ethyl-ether and 20 ml HCl in ethyl-ether (~5 N) and the precipitated product filtered off, washed with ethyl-ether and dried to yield the title compound: