Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)S(O[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=O)=O.[Cl-].[Li+].C[Sn](C)C.C[Sn](C)C.[F-].[K+].CCOC(C)=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.O1CCOCC1>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1
Reactant: O=S(=O)(Oc1ccccn1)C(F)(F)F
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccccn2)c1
Yield: 48 %

Procedure:
Methyl 3-bromophenylacetate (25 g, 0.109 mol), 2-(trifluoro-methylsulfonyloxy)-pyridine (24.8 g, 0.109 mol), anhydrous lithium chloride (13.89 g, 0.3275 mol), and tetrakis(triphenylphosphine)palladium (6.31 g, 0.0055 mol) were combined, followed by hexamethylditin (35.8 g, 0.109 mol) and anhydrous dioxane (300 ml). The mixture was stirred at reflux for 16h, cooled, and poured into 1:1 saturated KF-EtOAc (1.6 L). The mixture was stirred at RT for 2 h, filtered, and the filtrate was washed with saturated aqueous NaHCO3 (200 ml) and with brine (200 ml), dried (MgSO4), and concentrated in vacuo to give a brown oil. The residue was flash chromatographed (silica gel, 1:4 EtOAc:hexane) to give the title compound as a yellow oil (11.9 g. 48% yield): MS(ES+) 228.1 (MH+). cf. Tetrahedron Letters, 1995, 36, 9085-9088
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][CH2:14][N:5]2[C:6]3[C:11]([C:12]([CH3:13])=[C:4]2[C:3]1=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:15][CH2:14][N:5]2[C:6]3[C:11]([C:12]([CH3:13])=[C:4]2[C:3]1=[N:19][OH:20])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: NO
Reactant: Cc1c2n(c3ccccc13)CCC(C)(C)C2=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c2n(c3ccccc13)CCC(C)(C)C2=NO
Yield: 40.2 %

Procedure:
The title compound is prepared in an analogous manner to Step 1. A mixture of 6,7,8,9-tetrahydro-8,8,10-trimethylpyrido[1,2-a]indol-9-one (700 mg, 3.08 mmol, described in Example 1, Step 3), and hydroxylamine hydrochloride (420 mg, 6.04 mmol) was refluxed in pyridine (40 mL) for 21/2 hours. The reaction mixture was evaporated to dryness in vacuo and the residue suspended in water (20 mL). The insoluble components were extracted with ether (3×40 mL). The combined organic layer was washed with 5% hydrochloric acid, 10% sodium bicarbonate, and water. The separated organic layer was dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel (10 g). Elution with chloroform/hexane (1:1) afforded 300 mg (40%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](=[C:18]([CH3:20])[CH3:19])[CH3:17]>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:17])[C:18]([CH3:20])([CH3:19])[O:8][C:1]1([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=C(C)C
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC1(C)OC(c2ccccc2)(c2ccccc2)C1(C)C
Reaction time: 12 h

Procedure:
A benzene solution containing benzophenone and 2,3-dimethyl-but-2-ene was placed in a photochemical reaction apparatus made of Pyrex (registered trade mark) into which argon gas was sealed, and while stirring, was exposed to ultraviolet radiation for 12 hours, employing a high pressure mercury lamp. Subsequently, after removing the solvent, vacuum distillation was performed, whereby a targeted compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:12][C:8]1[CH:7]=[C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1cccc(F)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 50.4 %

Procedure:
Under nitrogen atmosphere, 45.0 g (0.209 mole) of 2-amino-3'-fluorobenzophenone was added in four portions at 15 min intervals to a stirred melt (120°-125° C.) of 38.2 g (0.241 mole) of 2-chloro-3-nitropyridine. The reaction mixture was heated at 120°-125° C. for one hr. and then at 145°-150° C. for 45 min. The mixture was cooled to 130° C. and 100 ml of toluene was added. The cooled mixture (room temperature) was diluted with 100 ml of ethyl acetate and extracted with 100 ml of 10% potassium hydroxide. The organic layer was extracted with three 100 ml portions of 3N hydrochloric acid, 100 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 35.5 g (50%) solid. The solid was dissolved in 200 ml of methylene chloride and the solution stirred with 50 g of fluorisil for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo. A 5 g portion of the residue was recrystallized from ethyl acetate-isopropyl ether to give 4.1 g of yellow-orange solid, m.p. 98°-101° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[O:1]([CH2:8][CH2:9][N:10]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnn(CCOc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C/c1cnn(CCOc2ccccc2)c1
Temperature: 60 °C
Yield: 90.6 %

Procedure:
To a solution of (E)-ethyl 3-(1-(2-phenoxyethyl)-1H-pyrazol-4-yl)acrylate (0.143 g, 0.5 mmol) in EtOH (6 mL) was added KOH (0.168 g, 3 mmol) in water (2 mL) and the solution was heated at 60° C. for 6 h. The reaction mixture was then evaporated under vacuum and water (10 mL) was added to the residue. This solution was acidified to pH 4 with aqueous 3N HCl and extracted with EtOAc. The organic extracts were washed with water and brine, dried over Na2SO4 and evaporated in vacuo to get the acid (0.117 g, 91%) as a white solid. ES+(M+H)+259
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:8][CH:7]=1)=[O:5].[Na].C(=O)([O-])O.[Na+]>CO>[C:17]([O:16][C:15](=[O:21])[NH:14][C@H:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([OH:5])[CH2:3][N:2]([CH3:1])[CH3:22])=[CH:11][CH:10]=1)[CH3:13])([CH3:19])([CH3:18])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.3 mg of the compound [1-4] was dissolved in 1.5 mL of methanol, 16.2 mg of sodium boronhydride was added thereto, and the mixture was stirred for 30 minutes at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the solution was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure, to obtain tert-butyl((1S)-1-{4-[2-(dimethylamino)-1-hydroxyethyl]phenyl}ethyl)carbamate [1-5] (hereinafter, referred to as the compound [1-5]). The compound [1-5] was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C@H:29]([CH3:30])[CH2:28][N:27]([C:31](=[O:34])[CH2:32]Br)[C@@H:26]([CH3:35])[CH2:25]2)=[C:20]([CH:36]=[CH:37][CH3:38])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][O:42][C:41]2[CH:45]=[C:46]([C:49]3([CH3:56])[NH:53][C:52](=[O:54])[NH:51][C:50]3=[O:55])[CH:47]=[CH:48][C:40]1=2>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]([CH3:30])[CH2:28][N:27]([C:31](=[O:34])[CH2:32][N:51]3[C:50](=[O:55])[C@@:49]([C:46]4[CH:47]=[CH:48][C:40]5[O:39][CH2:44][CH2:43][O:42][C:41]=5[CH:45]=4)([CH3:56])[NH:53][C:52]3=[O:54])[C@H:26]([CH3:35])[CH2:25]2)=[C:20](/[CH:36]=[CH:37]\[CH3:38])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@H](C)N(C(=O)CBr)C[C@H]1C
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CN2C(=O)N[C@@](C)(c3ccc4c(c3)OCCO4)C2=O)CC1C

Procedure:
1-((2S,5R)-4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl) phenyl}-2,5-dimethylpiperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:32][NH:33][CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:33]([CH3:34])[CH3:32])=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.4 g, about 0.9 mmol), dimethylamine hydrochloride (0.095 g, 1.17 mmol), DIEA (N,N-diisopropylethylamine, the same below) (0.18 mL, 1.04 mmol) and HATU (2-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, the same below) (0.342 g, 0.899 mmol) were added to a mixed solvent of DMF (dimethylformamide) (6.5 mL) and dichloromethane (6.5 mL). The mixture was stirred at room temperature for 3 hr and water was added.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C@:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:32])([F:31])[O:17][C:18]1[CH:30]=[CH:29][C:21]([O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].[Cl-].[NH4+].O.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C1(C)C=CC=CC=1>[C:42]1([CH3:52])[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:49])=[O:50])=[CH:46][CH:47]=1.[CH3:12][C@:8]([OH:11])([CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([N:26]2[CH2:27][CH2:28][CH:23]([O:22][C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:31])[F:32])=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)[CH2:9][OH:10]
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: C[C@@](O)(CO)COc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@](O)(CO)COc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
(R)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (20.0 kg, 76.6 mol), 4-[4-(trifluoromethoxy)phenoxy]piperidine (22.0 kg, 84.3 mol), tris(dibenzylideneacetone)dipalladium (0) (175 g, 0.19 mol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (195 g, 0.46 mol), sodium tert-butoxide (8.46 kg, 88.0 mol), and toluene (240 ml) were mixed, followed by stirring under an argon atmosphere at 70° C. for 3 hours. After cooling, an ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with toluene. Isopropanol was flowed therein, and p-toluenesulfonic acid monohydrate (16.0 kg, 84.1 mol) was added thereto, followed by stirring. The precipitated crystals thus obtained were collected by filtration and dried, obtaining 40.3 kg of (R)-2-methyl-3-(4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenoxy)propane-1,2-diol p-toluenesulfonic acid salt (yield: 85.7%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:1]1[C:10]2[CH:9]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCc2cccnc21
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione was prepared following the general procedure B for reductive amination. To a solution of 5,6,7,8-Tetrahydro-quinolin-8-ylamine (1.0609 g, 7.1 mmol) and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.4079 g, 6.8 mmol) (prepared according to the procedure for COMPOUND 18) in methylene chloride (64 mL) was added NaBH(OAc)3 (4.07 g, 19.2 mmol) and the reaction stirred at room temperature for two hours. The reaction was quenched with 1N NaOH (45 mL), extracted with methylene chloride (2×55 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—MeOH—NH4OH) provided 1.16 g (52%) of 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.57-1.66 (m, 3H), 1.69-1.84 (m, 4H), 1.93-2.03 (m, 1H), 2.07-2.13 (m, 1H), 2.69-2.86 (m, 4H), 3.70-3.77 (m, 3H), 7.03-7.07 (m, 1H), 7.35 (d, 1H, J=7.2 Hz), 7.67-7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.37 (d, 1H, J=3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
Tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(3-fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]2=[C:13]3[N:18]([CH:19]=[C:11]2[C:10](=[O:20])[NH:9][N:8]=1)[CH2:17][CH2:16][CH2:15][CH2:14]3.Br[C:22]1[N:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:23]=1[CH:24]=[O:25].N(CC(O)=O)C>[Cu]Br.O1CCOCC1>[Cl:30][C:26]1[C:23]([CH:24]=[O:25])=[C:22]([N:9]2[C:10](=[O:20])[C:11]3=[CH:19][N:18]4[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)=[C:12]3[CH:7]=[N:8]2)[N:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]ncc2c3n(cc12)CCCC3
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Cu]Br
Agent: CNCC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Temperature: 95 °C
Yield: 29.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), potassium carbonate (1.5 g, 10.6 mmol), 7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-4(3H)-one 192b (1.0 g, 5.3 mmol), and 2-bromo-4-chloronicotinaldehyde (3.5 g, 15.9 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, copper(I) bromide (75.0 mg, 0.53 mmol) and sarcosine (47.0 mg, 0.53 mmol) were added, and the reaction mixture was heated at 95° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between methylene chloride (60 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 ethyl acetate/petroleum ether to afford 192c as a brown solid (521 mg, 30%). MS-ESI: [M+H]+ 329.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2ccc(Cl)cc2)c1
Reaction time: 8 h

Procedure:
p-Chlorothiophenol (4.52 g., 31.4 mmoles) was reacted with 5-bromo-furan-3-carboxylic acid according to the procedure of Example 15, except that the total volume of dimethylformamide was 85 ml., and the reflux period was 8 hours. The reaction mixture was cooled, filtered, the filtrate diluted with 500 ml. of water and insolubles removed by filtration. The latter filtrate was made acidic with 6 N hydrochloric acid, product was extracted into ethyl acetate and recovered by evaporation to an oil, crystallized by trituration with water (860 mg.). Two crystallizations from methanol/water gave purified 5-(4-chlorophenylthio)furan-3-carboxylic acid (150 mg., m.p. 142°-145° C., m/e 254). Analysis: Calcd. for C11H7O3SCl; C, 51.87; H, 2.77. Found: C, 51.97; H, 2.99.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: COC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a stirred solution of methyl 1-acetyl-1H-indazole-5-carboxylate (1.16 g, 5.31 mmol) in methanol (10 mL) is added HCl (10 mL of a 6.0 M aqueous solution). The mixture is stirred at rt overnight. The methanol is removed in vacuo, and the remaining aqueous solution is basified with 30% aqueous NH4OH to pH=8. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to afford 900 mg (96%) of methyl 1H-indazole-5-carboxylate as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 13.4, 8.5, 8.3, 7.9, 7.6, 3.9.
Reaction SMILES: O[CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[F:35][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
tert-Butyl 3-hydroxy-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate described in Production Example 6-2 (518 mg, 1.54 mmol) was dissolved in dichloromethane (15 mL), [bis-(2-methoxyethyl)amino]sulfur trifluoride (0.313 mL, 1.70 mmol) was added at −78° C. over 3 minutes, and the mixture was stirred for 1 hour while warming to room temperature. A saturated aqueous sodium bicarbonate solution and ethyl acetate were serially added to the reaction mixture. The aqueous layer was extracted with ethyl acetate three times and then the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:2) to obtain the title compound (402 mg, 77%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]([NH:36][CH2:37][CH2:38][OH:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:36]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:37][CH2:38][OH:39])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CC(C)(C)NCCO
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N(CCO)C(C)(C)C)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 28.1 mg (0.24 mmol) 2-(tert-butylamino)-ethanol. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with diethyl ether (Et2O) to give 32 mg (48.7%) product as an orange powder. MS (ESI) m/z 548.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[O:2].[CH3:13][Mg]Br>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH3:13]
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccc(C=O)nc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a −78° C. solution of methyl 6-formylnicotinate (0.300 g, 1.82 mmol) in tetrahydrofuran (6 mL) was added methylmagnesium bromide (0.787 mL, 3M in THF, 2.36 mmol) over 20 minutes. The solution was warmed to 0° C. and stirred for 2 hours. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC gave methyl 6-(1-hydroxyethyl)nicotinate (230 mg, 70%) as a red oil. 1H NMR (400 MHz, CD3OD, δ): 8.93 (m, 1H), 8.26-8.29 (m, 1H), 7.59 (d, 1H), 4.73-4.83 (m, 1H), 3.84 (s, 3H), 1.37 (d, 3H).