Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20](O)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NOC1CCCCO1
Reactant: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)O)S(C)(=O)=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
4-[4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (190 mg, 0.451 mmol) and CDMT (95.6 mg, 0.539 mmol) were charged into a flask. The flask was flushed with nitrogen and 2-MeTHF (10 ml) was added, followed by NMM (64 uL, 0.581 mmol). The reaction mixture was stirred at RT for 1 hour. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (64 mg, 0.539 mmol) was added to the reaction mixture and stirred for 16 hours at RT. Water (25 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml). The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was purified by chromatography on silica gel (70% heptane:30% ethyl acetate to 100% ethyl acetate) to afford a white solid (220 mg, 79%). MS (LC/MS) m/z 511.1 (M−1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.93 (t, J=7.02 Hz, 3H) 1.12-1.42 (m, 9H) 1.49-1.99 (m, 10H) 2.25-2.43 (m, 1H) 2.45-2.64 (m, 1H) 3.12 (d, J=5.07 Hz, 3H) 3.51-3.68 (m, 2H) 3.82-4.03 (m, 4H) 4.08-4.26 (m, 2H) 5.03-5.14 (m, 1H) 5.94 (d, J=2.54 Hz, 1H) 6.07-6.21 (m, 1H) 7.45-7.60 (m, 1H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:15])[CH2:7][N:6]1C(OC)=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.O.[OH-].[Na+]>Cl>[CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:15])[CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)N1Cc2cccc(C)c2CC1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1CC(CC(C)C)NC2
Yield: 83.6 %

Procedure:
A solution of 20 mg of methyl 3-isobutyl-5-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate in hydrochloric acid (0.8 mL)-acetic acid (0.3 mL) was reacted at 90° C. for 48 hours. Under ice-cooling, the reaction liquid was diluted by addition of water, alkalized with 5 N sodium hydroxide, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by PLC (chloroform:ammonia saturated methanol=20:1) to obtain 13 mg (yield 84%) of a title compound as a light yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl.[CH3:13][O:14][C:15]1[C:19]([NH2:20])=[CH:18][N:17]([CH3:21])[N:16]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:20][C:19]2[C:15]([O:14][CH3:13])=[N:16][N:17]([CH3:21])[CH:18]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: COc1nn(C)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A suspension of 6-chloro-2-fluoro-9H-purine (88% potency, 5.90 kg, 30.20 mol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (98% potency, 5.55 kg, 33.22 mol, 1.10 eq), and sodium bicarbonate (10.1 kg, 120.81 mol, 4.00 eq) in EtOAc (106 L) was stirred at 50° C. for 12 hr. The reaction mixture was then cooled to 20° C., granulated for 1 hr, filtered, and the solids were washed with EtOAc (18 L) and dried on the filter. The crude product was charged back into the reactor and suspended in water (106 L) and stirred at 35° C. for 2 hr. The resulting slurry was cooled to 20° C. and the desired product was isolated by filtration and the cake was washed with water (30 L) and then with EtOAc (30 L) and dried for 16 hr at 50° C. to give the title compound (6.26 kg, 23.8 mol, 79% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3 H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].[C:26](Cl)(=[O:28])[CH3:27].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:26]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
29.9 g (0.09 mol) of III-15 was dissolved in a mixed solution of 150 ml of toluene and 50 ml of pyridine, followed by addition of 9.42 g (0.12 mol) of acetyl chloride at 15°-20° C. over a period of 2 hours. The mixture was maintained at the same temperature for 2 hours and then at 40°-45° C. for another 2 hours. The reaction mixture was cooled below 10° C. and added with 300 ml of 3N hydrochloric acid. After separating the liquid phase, the organic layer was washed with water, 5% sodium hydrogencarbonate and water successively in that order and concentrated under reduced pressure. The residue was purified by column chromatography to give 33.0 g (98% yield) of benzyl 4'-(1-acetoxyethyl)-4-biphenylcarboxylate (IV-15).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH:40]1([C:46]2[S:50][C:49]([NH2:51])=[N:48][N:47]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>C1COCC1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:51][C:49]1[S:50][C:46]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:47][N:48]=1)=[O:12])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1nnc(C2CCCCC2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2nnc(C3CCCCC3)s2)c1
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a mixture of 5-(aminosulfonyl)-2-chlorobenzoic acid (33 mg, 0.14 mmol) in THF in a vial was added PS-DCC (0.1 g, 0.155 mmol), PS-HOBt (0.12 g, 0.159 mmol) and then above crude 5-cyclohexyl-1,3,4-thiadiazol-2-amine (30 mg, 0.16 mmol). The reaction mixture in the vial was shaken for overnight. The reaction slurry was diluted with more THF, and filtrated to remove polymer bound reagents. The filtrate was concentrated, and then the residue was purified by using a Gilson preparative HPLC system with a Water Xterra (C-18) column 100 mm by 50 mm ID, eluting with 2% B to 90% B in 10 minutes, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-(aminosulfonyl)-2-chloro-N-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)benzamide (2.75 mg).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:21])=[C:14]2[C:15]([CH3:20])=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O

Procedure:
14.8 g of [[(1-ethyl-3-methyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.05 mol) is dissolved in 50 g of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while continuously distilling off the resulting ethanol. The last part of the alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionation column in vacuo. The 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p.0.1-0.5 125°-129°, yield 10.7 g = 86% of theory, m.p. 91-93°. The compound is recrystallized from ligroin (90°-100°), and has a melting point of 93°-94°. Hydrolysis of this product with aqueous sodium hydroxide yields 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, m.p. 212°-213°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]=[C:11]([CH2:17][CH3:18])[CH:10]=2)[N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[N:32][CH:33]=1>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]=[C:11]([CH2:17][CH3:18])[CH:10]=2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:30]3[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=3)[CH:20]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(F)c1
Reactant: CCc1cc(C2(c3ccc(F)c(Br)c3)N=C(N)N(C)C2=O)cc(CC)n1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C2(c3ccc(F)c(-c4cncc(F)c4)c3)N=C(N)N(C)C2=O)cc(CC)n1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
A mixture of 2-amino-5-(3-bromo-4-fluorophenyl]-5-(2,6-diethyl-pyridin-4-yl)-3-methyl-3,5-dihydro-imidazol-4-one (0.12 g, 0.286 mmol), 5-fluoropyridin-3-yl(tributly)tin (0.166 g, 0.43 mmol) and bis(triphenylphosphino)palladium(II) chloride (0.016 g, 0.023 mmol) in DMF (5 mL) was degassed and heated at 150° C. for 0.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and 2% aqueous lithium chloride (20 mL). The organic layer was separated, washed with 2% aqueous lithium chloride, dried over sodium sulfate, filtered, and concentrated. Purification of the resultant residue by flash chromatography (silica, 97:3:0.25 methylene chloride/methanol/concentrated ammonium hydroxide) afforded the title product (0.085 g, 68%) as a white solid, mp 155-157° C.; 1H NMR (300 MHz, CD3OD) 8.55 (d, J=1.5 Hz, 1H), 8.49 (d, J=2.7 Hz, 1H), 7.82 (d, J=9.6 Hz, 1H), 7.60-7.57 (m, 2H), 7.27 (dd, J=10.2, 8.7 Hz, 1H), 7.15 (s, 2H), 3.13 (s, 3H), 2.74 (q, J=7.5 Hz, 4H), 1.23 (t, J=7.5 Hz, 6H); IR (ATR) 3064, 2969, 2935, 1733, 1670, 1597, 1459, 1412, 1328, 1228, 989, 881, 783, 702 cm−1; ESI MS m/z 436 [C24H23F2N5O+H]+. Anal. Calcd for C24H23F2N5O: C, 66.19; H, 5.32; N, 16.08.
Reaction SMILES: [CH2:1]([N:7]1[C:14]([C:15]2[S:16][C:17](Br)=[CH:18][CH:19]=2)=[C:13]2[C:9](=[C:10]([C:28]3[S:29][C:30](Br)=[CH:31][CH:32]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2=[O:21])[C:8]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cu][C:36]#[N:37].[CH3:38][N:39](C=O)C>>[CH2:1]([N:7]1[C:14]([C:15]2[S:16][C:17]([C:38]#[N:39])=[CH:18][CH:19]=2)=[C:13]2[C:9](=[C:10]([C:28]3[S:29][C:30]([C:36]#[N:37])=[CH:31][CH:32]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2=[O:21])[C:8]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: CCCCCCN1C(=O)C2=C(c3ccc(Br)s3)N(CCCCCC)C(=O)C2=C1c1ccc(Br)s1
Product: CCCCCCN1C(=O)C2=C(c3ccc(C#N)s3)N(CCCCCC)C(=O)C2=C1c1ccc(C#N)s1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
The synthesis of 2,5-di-n-hexyl-3,6-bis(5-bromo-thiophen-2-yl)pyrrolo[3,4-c]-pyrrole-1,4-dione is done in analogy to Zhou et al., Macromolecules 43 (2010) 821-826. 2,5-Di-n-hexyl-3,6-bis(5-bromo-thiophen-2-yl)pyrrolo[3,4-c]-pyrrole-1,4-dione (237 mg, 0.378 mmol) and copper(I)-cyanide (1.50 g, 17.0 mmol) are placed in a 25 mL-flask under argon. Dry DMF (10 mL) is added and the mixture is stirred at 130° C. for 4 h. The solvent is removed under reduced pressure and the residual solid is extracted with chloroform (250 mL). After removing the solvent the crude product is purified by column chromatography (dichloromethane). A violet solid is obtained (52 mg, 27%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][OH:14])[O:4]1.O[N:16]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][O:14][NH2:16])[O:4]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC1O[C@H](CON)[C@H]2OC(C)(C)O[C@@H]12
Yield: 50 %

Procedure:
The title compound was prepared using the procedure described for Example 2K by using ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.04 g, 10 mmol), CH2Cl2 (25 mL), 2-hydroxyisoindoline-1,3-dione (2.0 g, 12 mmol), triphenylphosphine (4.0 g, 15 mmol), diisopropylazodicarboxylate (3.0 ml, 15 mmol) and hydrazine hydrate (2.0 mL, 20 mmol) to afford 1.12 g of 04(3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)hydroxylamine (2Y) (50%, over two steps) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 3H) 1.26 (s, 3H) 3.31 (s, 3H) 3.59-3.75 (m, 2H) 4.44 (t, J=7.20 Hz, 1H) 4.56 (d, J=5.81 Hz, 1H) 4.67 (d, J=6.06 Hz, 1H) 4.92-5.00 (m, 1H). MS (ES) [M+H] calculated for C9H18NO5, 220.11; found 220.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.C(OCC)(=O)C>ClCCl>[N+:28]([C:27]1[CH:22]=[CH:23][C:24]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccc([N+](=O)[O-])cc1
Yield: 16 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using p-nitrophenol (18 mg, 0.13 mmol) as the coupling partner. Chromatography (1:1 ethyl aceate:dichloromethane) through SiO2 yielded 11 mg (16%) of the titled compound. ESI-MS m/z 413 (MH+), 411 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:17][N:18]1[CH2:22]C[C@H:20](O)[CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH2:19][CH2:20][C@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:22]1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN1CC[C@H](O)C1
Solvent: Cc1ccccc1
Product: CN1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Yield: 24.9 %

Procedure:
Prepared as described in Intermediate I-5 from 0.98 g (0.00385 mol) of 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester in 30 ml of toluene, 0.39 g (0.00385 mol) of (3S)-1-methylpyrrolidin-3-ol (Intermediate I-20) and 0.108 g (0.0027 mol) of HNa (60% dispersion in mineral oil). The yield was 0.31 g (25%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:23][C:9]1[C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC1(C)OC(c2ccc(Cl)cc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(Cl)cc2)=C(Br)C1=O
Reaction time: 1 h
Yield: 51 %

Procedure:
To stirred solution of crude 5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (2.1 g, 13.0 mmol) in CHCl3 (15 mL), NBS (3.93 g, 22.10 mmol) was added portionwise at RT. The reaction mixture was stirred for 1 h and then diluted with DCM (100 mL). The combined organic layers were washed with water (50 mL) and brine (30 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (2.0 g, 51% over three steps) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23].O.Cl>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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)c(F)cc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)n1ccc2cc(C#CCCCO)c(F)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 455.2 %

Procedure:
A mixture of 3.04 g (9.67 mmol) 5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester, 670 mg (0.58 mmol) Pd(PPh3)4, and 111 mg (0.58 mmol) CuI in 25 ml of piperidine was heated to 60° C., treated with 1.61 ml (1.80 mmol) 4-pentyne-1-ol and stirred at 80° C. for 2 hrs. After cooling to room temperature the mixture was poured into water, acidified with 2M aqueous HCl and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2 gave 2.6 g (85%) of 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butyl ester as a viscous orange oil, MS: 318 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[N-:24]=[N+:25]=[N-:26].[Na+].[O:28]=[C:29]1[O:35][C@H:34]([C@H:36](CO)O)[C:32]([O-])=[C:30]1O.[Na+].BrC(C)C(OCC)=O>[Cu]I.O>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:24]=[N:25][N:26]([CH:30]([CH3:32])[C:29]([O:35][CH2:34][CH3:36])=[O:28])[CH:18]=3)=[CH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)nc1
Agent: [Cu]I
Agent: CCOC(=O)C(C)Br
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)n1cc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in a similar manner as that described for Example 10, step 4. Into a 25-mL round-bottom flask equipped with a magnetic stirbar was added 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-5-ethynylpyrimidine (130 mg, 0.35 mmol), sodium azide (23 mg, 0.35 mmol) tert-butanol (1.5 mL), water (0.7 mL), copper(I) iodide (4 mg, 0.02 mmol) and sodium ascorbate (9 mg, 0.04 mmol). The resulting suspension was treated with dropwise addition of ethyl 2-bromopropionate (45 μL, 0.35 mmol) and stirred at room temperature for 16 h overnight. The mixture was poured into a 125 mL separatory funnel containing water (75 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. Purification by column chromatography through silica gel, eluting with 5% EtOAc in hexanes to 55% EtOAc in hexanes as a gradient gave the desired product as a beige solid.
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[O:1]1[CH:5]([CH2:6][NH:7][C:26](=[O:27])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2ccc3ccccc3c2O1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2ccc3ccccc3c2O1)OCc1ccccc1
Yield: 90.4 %

Procedure:
Treatment of (±)-1-(2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine (1.19 g, 5.97 mmol) with diisopropylethylamine (0.849 g, 6.57 mmol) followed by benzyl chloroformate (1.07 g, 6.27 mmol) generally according to the procedure described for Intermediate 7 afforded 1.80 g (90%) of (±)-benzyl 2,3-dihydronaphtho[1,2-b]furan-2-ylmethylcarbamate as a white solid. Rf=0.47 (silica, ethyl acetate:hexanes 1:4); mp 110-112° C.; Anal. calcd. for C21H19NO3: C, 75.66; H, 5.74; N, 4.2. Found: C, 75.4; H, 5.57; N, 4.12. Chiral HPLC separation of (±)-benzyl 2,3-dihydronaphtho[1,2-b]furan-2-ylmethylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt=19.572 min, Chiralcel OJ, ethanol); Fraction 2 (Rt=30.782 min, Chiralcel OJ, ethanol).
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)CC.[ClH:28].[N:29]([O-])=O.[Na+].N(O)=O>O.C(O)(=O)C>[Cl-:28].[CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([N+:17]#[N:29])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=N[O-]
Reactant: CCCCCCCCCCCCc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cl
Agent: O=NO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCC(=O)O
Solvent: O
Product: CCCCCCCCCCCCc1ccc([N+]#N)c([N+](=O)[O-])c1
Product: [Cl-]
Temperature: 0 °C

Procedure:
4-Dodecyl-2-nitroaniline (61.20 g; 20 mol) was stirred with glacial acetic acid (200 ml) and propionic acid (200 ml) containing concentrated hydrochloric acid SGl.18 (100 ml) at 70° C. The amber solution was cooled to 0° C. and a solution of sodium nitrite (14.00 g; 0.203 mol) in water (100 ml) was added dropwise over 1 hour at 0° C. After stirring for 2 hours at 0° C. the excess nitrous acid was destroyed by the addition of 10% sulphamic acid to give an orange mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH2:24])=[NH:23].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:24]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[N:23]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)C#Cc1cncc(Br)c1
Reactant: N=C(N)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2cncc(Br)c2)nc(-c2ccccn2)n1

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-4,4-dimethyl-pent-1-yn-3-one (1 eq, 770 mg, 2.89 mmol) in THF (12 ml) is added pyridine-2-carboxamidine (1.5 eq, 684 mg, 4.34 mmol) and Na2CO3 (2.4 eq, 736 mg, 6.94 mmol). The resulting mixture is heated using microwave radiation for 1 h at 150° C. The solvent is removed in vacuo and the residue is partitioned between sat. aqueous NaHCO3 solution and DCM. The organic portion is dried (MgSO4) and concentrated in vacuo. The resulting residue is purified using column chromatography (DCM/MeOH) to give the title compound; [M+H]+=369/371.