Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][OH:30])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][OH:30])=[CH:24][CH:23]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCc1ccc(Br)cc1
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCC1Cc2ccc(-c3ccc(CCO)cc3)cc2C1
Yield: 68 %

Procedure:
2.74 g (10.0 mmol) of 2-octylindane-5-boronic acid, 2.0 g (10.0 mmol) of 2-(4-bromophenyl) ethanol, 0.38 g of tetrakis (triphenylphosphine) palladium, 15 ml of 2M-sodium carbonate solution, 15 ml of toluene and 10 ml of ethanol were heated at 80° C. for 6 hours under presence of nitrogen. After reactions had been completed, extraction with toluene was performed. Then, the extracted solution was dried with anhydrous sodium sulfate. The solvent was removed by filtration, and then refining was performed by re-crystallization (hexane/ethanol) so that 2.40 g of 2-{4-(2-octylindane-5-yl) phenyl}ethanol was obtained (yield 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.C(#N)N(C)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[S:11][C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:9])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Br)cc3)s2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: O=C(c1ccc(Br)cc1)c1ccc(-c2ccc(CBr)cc2)s1
Yield: 84.7 %

Procedure:
0.5 g of (4-bromophenyl)-(5-p-tolyl-thiophen-2-yl)-methanone and 262 mg of N-bromosuccinimide in 20 ml of carbon tetrachloride are held at reflux for 19 hrs. after the addition of a spatula tip of azaisobutyronitrile, concentrated and the residue is chromatographed on silica gel (methylene chloride/hexane). 517 mg of [5-(4-bromomethyl-phenyl)-thiophen-2-yl]-4-bromophenyl-methanone, m.p. 184° C. (decomposition), are isolated.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:2](=[O:3])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)OCc1ccccc1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCc1ccccc1
Yield: 84 %

Procedure:
Using the general method of Example 55, benzyl chloroformate (83 μL, 0.58 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.18 g of benzyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:16]([O:18][CH2:20][CH3:21])=[O:17])[CH2:13][CH2:14][CH2:15]3)[CH:8]=2)[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1Nc2ccc(C3(C(=O)O)CCC3)cc2C1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3)CCC1
Temperature: 80 °C
Yield: 334.1 %

Procedure:
7.2 g of 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylic acid are dissolved in 100 ml of ethanol, and 500 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h and subsequently evaporated in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate, and the aqueous phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase), giving 2.4 g (30%) of ethyl 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylate;
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][O:9][N:10]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[N:11]1>[OH-].[Na+]>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[CH2:6][CH2:7][CH2:8][O:9][N:10]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]1
Reactant: COC(=O)c1cnn(OCCCC2OCCO2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnn(OCCCC2OCCO2)c1

Procedure:
151 g of the above product from (a) are stirred with 650 ml of 2N sodium hydroxide solution at 90° C. until a clear solution has formed. The solution is cooled and then washed with 200 ml of methylene chloride, the aqueous phase is acidified with concentrated hydrochloric acid and extracted several times with methylene chloride, and the extract is dried and evaporated down to give a colorless residue which crystallizes spontaneously. Yield: 129 g (88% of theory, based on methyl 1-hydroxypyrazole-4-carboxylate). M.p.: 85° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].O=CC(Cl)(Cl)Cl.[Cl-].[OH:19][NH3+:20].Cl.NC1C=CC=CC=1>>[CH:8]1[CH:7]=[CH:6][C:11]([NH:1][C:2](/[CH:4]=[N:20]/[OH:19])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: [NH3+]O
Agent: Cl
Agent: O=CC(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: Nc1ccccc1
Product: O=C(/C=N/O)Nc1ccccc1

Procedure:
The isatin derivative (9) can be synthesized, for example, as shown in the following reaction scheme. That is, an aqueous solution obtained by adding chloral and hydroxylammonium chloride to hydrochloride of an aniline derivative (10) as a starting material is reacted for 0.5 to 2 hours with heating at 70° to 110° C. to give an isonitrosoacetanilide derivative, and this product is cyclized with concentrated sulfuric acid and hydrolyzed to give an isatin derivative (9). ##STR10## wherein R1A to R1D are as defined above.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH:59]1[C:71]2[NH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:63]=2[C:62]([C:72]2[CH:73]=[CH:74][C:75]([C:78]#[N:79])=[N:76][CH:77]=2)=[CH:61][CH:60]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:70]2[C:71]3[CH:59]=[CH:60][CH:61]=[C:62]([C:72]4[CH:73]=[CH:74][C:75]([C:78]#[N:79])=[N:76][CH:77]=4)[C:63]=3[C:64]3[C:69]2=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:3][C:4]=1[F:10])#[N:7]
Reactant: N#Cc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C#N)c(F)c2)cn1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
0.267 g of 4-bromo-2-fluorobenzonitrile, 1.1 g of caesium carbonate, 0.06 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 0.02 g of palladium acetate are successively added, under argon, to a solution of 0.24 g of 5-(9H-carbazol-4-yl)pyridine-2-carbonitrile in 10 ml of dioxane. The reaction mixture is refluxed for 3 hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 0.2 g of 5-[9-(4-cyano-3-fluorophenyl)-9H-carbazol-4-yl]pyridine-2-carbonitrile in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: CC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:24]=[C:25]([O:29][CH3:30])[CH:26]=[CH:27][CH:28]=1.[C:31]1([C@H:37]([OH:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[Cu]I.C1(C)C=CC=CC=1>[C:31]1([C@H:37]([O:39][C:23]2[CH:24]=[C:25]([O:29][CH3:30])[CH:26]=[CH:27][CH:28]=2)[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@@H](O)c1ccccc1
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: Cc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(O[C@H](C)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 32 h
Yield: 76 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 5-methyl-1,10-phenanthroline (39 mg, 0.20 mmol, 20 mol %), Cs2CO3 (652 mg, 2.0 mmol), 3-iodoanisole (119 μL, 1.0 mmol), (R)-(+)-1-phenylethanol (205 μL, 1.7 mmol, >99% ee) and toluene (1 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 32 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane/ethyl acetate 30:1) provided 173 mg (76% yield, 98% ee) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([OH:25])[CH:23]=[CH2:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[O:33]1[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][O:25][CH:22]([CH:23]=[CH2:24])[CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:32]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: C=CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)N1CCOCC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a reactor with 1-(trityloxy)but-3-en-2-ol (41.6 g, 0.111 mol, 1.0 equiv.) was charged toluene (146 mL). The resulting solution was cooled to 0-5° C. and tetra-n-butylammonium hydrogen sulfate (7.52 g, 0.0222 mol, 0.20 equiv.) was charged. 4-(Chloroacetyl)morpholine (18.1 g, 0.111 mol, 1.00 equiv.) was added at 0-5° C. Sodium hydroxide (50% wt. in water; 88.6 g, 1.10 mol, 10 equiv.) was cooled to 15° C. and charged to the reaction mixture with T<10° C. The reaction mixture was stirred for 1 hr at T<15° C. and monitored for consumption of 1-(trityloxy)but-3-en-2-ol (target>99%). To the reaction mixture was charged 2-methoxy-2-methylpropane (146 mL) and water (146 mL) with T<20° C. The organics were washed with 18% aq. NaCl (73 mL) and sat. aq NH4Cl (21 mL). The organics were filtered over Celite (10.4 g) to remove particulates and rinsed with 2-methoxy-2-methylpropane (83 mL). The solvents were evaporated under vacuum T<30° C. to afford a white solid on standing (55.0 g, 98.7% yield accounting for residual solvents). 1H NMR (500 MHz, CDCl3) δ ppm 7.46-7.41 (m, 6H), 7.32-7.25 (m, 6H), 7.25-7.18 (m, 3H), 5.79-5.68 (m, 1H), 5.28 (d, J=17.0 Hz, 1H), 5.26 (d, J=10.1 Hz, 1H), 4.20 (d, J=12.7 Hz, 1H), 4.10 (d, J=12.7 Hz, 1H), 3.97-3.88 (m, 1H), 3.69-3.47 (m, 8H), 3.25 (dd, J=9.9, 6.5 Hz, 1H), 3.17 (dd, J=9.9, 4.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 167.84, 143.84, 134.84, 128.67, 127.78, 127.04, 119.06, 86.73, 81.07, 68.78, 66.78, 66.34, 45.94, 42.16.
Reaction SMILES: O1C2C=CC(C3C=C(C(O)=O)C(=O)N(CC4C=CC(F)=CC=4)N=3)=CC=2C=C1.[C:28]([C:31]1[C:32](=[O:56])[N:33]([CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[N:34]=[C:35]([C:37]2[CH:38]=[CH:39][C:40]3[O:44][CH2:43][CH2:42][C:41]=3[CH:45]=2)[CH:36]=1)(O)=[O:29]>>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][CH2:47][CH2:46][N:33]1[C:32](=[O:56])[C:31]([CH2:28][OH:29])=[CH:36][C:35]([C:37]2[CH:38]=[CH:39][C:40]3[O:44][CH2:43][CH2:42][C:41]=3[CH:45]=2)=[N:34]1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccccc2Cl)c1=O
Agent: O=C(O)c1cc(-c2ccc3occc3c2)nn(Cc2ccc(F)cc2)c1=O
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CCCc1ccccc1Cl
Yield: 49.6 %

Procedure:
The general procedure of Example 1 (4) was carried out by use of 4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, to thereby yield the title compound as a yellow oil (yield: 49.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][O:14][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:8][C:7]=1[F:15]
Reactant: OCc1cc(F)c(Oc2cc(F)cc(F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cc(F)cc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3,5-difluorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccn1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1-c1ccccn1
Reaction time: 0.17 h

Procedure:
3-(3-Bromo-phenylsulfanyl)-6-chloro-2-methyl-1H-indole (0.500 g, 1.4 mmol) along with K2CO3 (0.488 g, 3.5 mmol) and 2-fluoropyridine (87 μL, 2.1 mmol) were dissolved in DMF (2 mL) and reacted in a microwave at 200° C. for 20 minutes. The reaction was returned to the microwave at 200° C. for an additional 10 minutes. Standard workup followed by silica gel chromatography (0-100% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([B:13]([OH:17])[OH:14])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ncc(B(O)O)cc1C(F)(F)F

Procedure:
5-bromo-3-(trifluoromethyl)pyridin-2-amine (9.85 mmol, commercially available), Bis(pinacolato)diboron (11.82 mmol), potassium acetate (1.4 g) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (200 mg, commercially available) was dissolved in dioxane (75 mL) under argon atmosphere. The reaction mixture was refluxed for 8 h. The reaction mixture was cooled, diluted with ethyl acetate (75 mL) and filtered. The filtrate was concentrated. The crude product was purified over silica gel using 0-10% ethyl acetate in petroleum ether to obtain the titled boronic acid derivative.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]1[O:63][NH2:64]>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[C:18]([NH:64][O:63][CH:58]2[CH2:59][CH2:60][CH2:61][CH2:62][O:57]2)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (670 mg, 1.77 mmol) in methylene chloride (18 mL) at ambient temperature was added 1, (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (474 mg, 2.47 mmol), 1-hydroxy benzotriazole monohydrate (487 mg, 3.18 mmol), triethylamine (443 uL, 3.18 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (310 mg, 2.65 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated to afford 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as an oil. 536.3 mg LCMS: (M−1) 477.3
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][C@H:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][C:13]([CH3:23])([CH3:22])[O:12]1)(C)C)(C)(C)C.C([Si](OCC[C@@H]1[C@@H](C2C=CC=CC=2)OC(C)(C)O1)(C)C)(C)(C)C>>[C:16]1([C@@H:15]2[O:14][C:13]([CH3:22])([CH3:23])[O:12][C@H:11]2[CH2:10][CH2:9][OH:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)O1
Agent: CC1(C)O[C@H](c2ccccc2)[C@@H](CCO[Si](C)(C)C(C)(C)C)O1
Product: CC1(C)O[C@@H](CCO)[C@H](c2ccccc2)O1
Yield: 80 %

Procedure:
The substantially same method as described in Example 285 was conducted, except that tert-butyl(2-((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation example 288) was used instead of that tert-butyl(2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation example 284), to obtain the title compound (0.4 g, 80˜95%)
Reaction SMILES: [ClH:1].[C:2]1([O:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:11]2[CH2:10][CH2:9][CH2:8]C[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]1([O:28]C2CCN(CC3C=CC=CC=3)C2)C2CCCCC=2C=CC=1>>[ClH:1].[CH3:18][O:28][C:3]1[C:2]([O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:8][CH2:9][CH2:10]2
Reactant: c1cc2c(c(OC3CCNC3)c1)CCCC2
Reactant: c1ccc(CN2CCC(Oc3cccc4c3CCCC4)C2)cc1
Agent: Cl
Product: COc1ccc2c(c1O[C@H]1CCNC1)CCC2

Procedure:
3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-pyrrolidine hydrochloride m.p. 207° C., starting from 3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine
Reaction SMILES: C(N1C2=CC3C(=CC2=C(C2SC(Br)=CC=2)C1=O)N(CCCCCC)C(=[O:25])C=3C1SC(Br)=CC=1)CCCCC.C(C(CCCCCCCCCC)C[N:49]1[C:56](C2SC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[C:55]2[C:51](=[C:52](C3SC(B4OC(C)(C)C(C)(C)O4)=CC=3)[N:53](CC(CCCCCCCC)CCCCCCCCCC)[C:54]2=[O:71])[C:50]1=O)CCCCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].BrC1SC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.CO.C1(C)C=CC=CC=1.O>[O:25]=[C:55]1[C:56]2[C:52]([CH:51]=[CH:50][N:49]=2)=[N:53][C:54]1=[O:71]
Reactant: CCCCCCCCCCC(CCCCCCCC)CN1C(=O)C2=C(c3ccc(B4OC(C)(C)C(C)(C)O4)s3)N(CC(CCCCCCCC)CCCCCCCCCC)C(=O)C2=C1c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CCCCCCN1C(=O)C(c2ccc(Br)s2)=c2cc3c(cc21)=C(c1ccc(Br)s1)C(=O)N3CCCCCC
Agent: [Pd]
Agent: Brc1cccs1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1nc2ccnc-2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 705.4 %

Procedure:
A mixture of 1,5-dihexyl-3,7-di-(5-bromothiophen-2-yl)-1H,5H-pyrrolo[2,3-f]indole-2,6-dione (0.100 g, 0.148 mmol), 2,5-dihydro-2,5-bis(2-octyldodecyl)-3,6-bis[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]-pyrrolo[3,4-c]pyrrole-1,4-dione (0.168 g, 0.150 mmol), Pd2(dba)3 (4.0 mg), tri-tert-butylphosphonium tetrafluoroborate (2.0 mg), K3PO4 (0.095 g) and toluene/H2O (8 mL/0.3 mL) was heated at reflux for 48 h. 2-bromothiophene (0.035 g, 0.22 mmol) in toluene (1 mL) was added and the resulting mixture was stirred for another 12 h. Then, after cooling to room temperature, the mixture was dropped into methanol to precipitate. After being filtered and dried, the precipitation was Soxhlet extracted with methanol, acetone, hexane, dichloromethane and chloroform in succession. The chloroform solution was concentrated and reprecipitated in methanol. The solid was filtered and dried to yield polymer (0.14 g, 70%) as a black solid.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18](Cl)(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[OH-].[NH4+:23]>O1CCCC1>[CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([NH2:23])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(N)(=O)=O
Temperature: 25 °C

Procedure:
A solution of the crude sulfonyl chloride from Example 13 in 150 ml of tetrahydrofuran was cooled to 0° and treated with 7.3 ml of concentrated aqueous ammonium hydroxide. The resulting suspension was allowed to warm to room temperature. Removal of the solvent in vacuo gave an oily residue which was triturated with 300 ml water. The precipitate was collected by filtration, washed with n-butyl chloride and dried to yield 9.3 g of 2-[(N,N-dimethylamino)sulfonyl]-6-(methoxycarbonyl)phenylmethanesulfonamide as a light yellow solid, m.p. 133°-142°; IR(nujol): 3400, 3310, 1720 cm-1 ; NMR (CDCl3 /DMSO-d6): δ 2.6 (6H, s, SO2N(CH3)2), 3.8 (3H, s, CO2CH3), 5.35 (2H, s, --CH2 --), 5.3-5.9 (2H, br s, NH2), 7.4-8.3 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[N:12][OH:13])[CH3:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][N:12]=[C:10]([C:3]1[C:4]([OH:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[CH3:11])(=[O:16])[CH3:15]
Reactant: CC(=NO)c1c(O)cc(C)cc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)ON=C(C)c1c(O)cc(C)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(2,6-dihydroxy-4-methylphenyl)ethanone oxime (Intermediate 17, 829 mg), acetic anhydride (2.6 ml, 27.5 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After the removal of the volatiles, the residue was washed with water, filtered and dried. This afforded 1.0 g of the title compound.