Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].CI.[CH:31](OC(C)C)(C)C>CN(C)C=O.O>[CH3:31][N:17]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:14]1[S:15][CH:16]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=2)[N:13]=1
Reactant: COC(=O)c1ccc(CNc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Reactant: CC(C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
Under an argon atmosphere, to a suspension of sodium hydride (content 60%, 26.4 g, 0.661 mol) in N,N-dimethylformamide (530 ml, 2.5 v/w) were successively added dropwise a solution of methyl 4-((4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate (212.4 g, 0.575 mol) obtained in Example 1(2) in N,N-dimethylformamide (743 ml, 3.5 v/w) and methyl iodide (41.2 ml, 0.661 mol) at 10° C. or below, and the mixture was stirred at room temperature for 2 hr. Sodium hydride (content 60%, 2.3 g, 0.057 mol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added dropwise to water (2120 ml, 10.0 v/w) at 10° C. or below, and, after stirring at room temperature for 30 min., diisopropyl ether (848 ml, 4.0 v/w) was added and the mixture was stirred for 2 hr. The precipitated crystals were collected by filtration, washed successively with diisopropyl ether (424 ml) and water (424 ml) and dried in vacuo to give the title compound (201.9 g, yield 91.4%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5](Cl)[Cl:6])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[Cl:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2]
Reactant: CCOC(OCC)C(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=CCl)OCC
Yield: 90 %

Procedure:
To a solution of dichloroacetaldehyde diethylacetal (25 g; 0.1336 mol) in 150 ml of THF cooled to 0° C. was added 17.99 g (0.16 mol) of potassium t-butoxide in 50 ml of THF. The ice-bath was removed, and the reaction mixture was allowed to reflux for 16 hr and cooled. The reaction mixture was filtered (through celite) and a pale yellow solution was concentrated in vacuo at 30° C. The residue was distilled to afford 18.1 g (90%) of 2-chloro-1,1-diethoxyethylene (Formula V: R3 =Cl; R4 =H; R5 =R6 =OC2H5), a colorless liquid, b.p. 70°-76° C./20-25 mm.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[S:9][CH:10]=[CH:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Product: O=C(Cc1ccc(F)cc1)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(4-fluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.71 (s, 2H) 7.18 (t, J=8.85 Hz, 2H) 7.41 (dd, J=8.54, 5.80 Hz, 2H) 7.48-7.65 (m, 4H) 7.63-7.78 (m, 2H) 8.36 (d, J=5.19 Hz, 1H) 11.80 (s, 1 H); MS (ESI) m/z 380 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH:14]=O)(C)(C)C.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[C:6](=[O:16])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)=[O:20])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccncc2[nH]c1=O
Temperature: 23 °C

Procedure:
A solution of 6-2 (2.20 g, 9.90 mmol, 1 equiv), diethyl malonate (3.00 mL, 19.8 mmol, 2.00 equiv), and piperidine (0.490 mL, 4.95 mmol, 0.500 equiv) in ethanol (50 mL) was heated at reflux for 20 h. The reaction mixture was allowed to cool to 23° C., then concentrated to about half its volume. The white crystals which formed were filtered and washed with cold ethanol (20 mL) to give 2-oxo-1,2-dihydro-[1,7]naphthyridine-3-carboxylic acid ethyl ester (6-3). 1H NMR (400 MHz, CDCl3) δ 12.15 (br s, 1H), 8.94 (s, 1H), 8.52 (d, 1H, J=5.2 Hz), 8.46 (s, 1H), 7.52 (d, 1H, J=5.2 Hz), 4.48 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz); TLC (EtOAc), Rf=0.13.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22](Br)[S:21]4)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+]>ClCCl.CO>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:28][CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Brc1nn2cc(-c3cc4c(OCc5ccccc5)cccc4o3)nc2s1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nn2cc(-c3cc4c(OCc5ccccc5)cccc4o3)nc2s1
Reaction time: 0.67 h

Procedure:
A solution of 6-(4-(benzyloxy)benzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Example 38E, 3.22 g, 7.55 mmol) in a mixture of dichloromethane (400 mL) and methanol (50 mL) was treated at 22° C. with 6.3 mL of a 25 wt. % solution of sodium methoxide in methanol (30.2 mmol) added in one portion. More methanol (45 mL) was added and the mixture was stirred for 40 min. The reaction mixture was quenched by the addition of 40 mL of 1 N hydrochloric acid followed by 10 ml of saturated sodium bicarbonate. The solvent was evaporated under reduced pressure and the residue was diluted with dichloromethane (400 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Crystallization of the white solid residue from 1,2-dichloroethane (30 mL) gave 2.19 g of the title material as a white solid. Chromatography of the mother liquors on silica gel (3×10 cm, elution with dichloromethane-ethyl acetate 0-1%) gave another 0.46 g of product (total yield 2.65 g, 93%). LC (Method A): 2.379 min. HRMS (ESI) calcd for C20H16N3O3S [M+H]+ m/z 378.0907, found 378.0911. 1H NMR (CDCl3, 600 MHz) δ ppm: 4.18 (s, 3H), 5.21 (s, 2H), 6.71 (dd, J=7.4 Hz and J=0.95 Hz, 1H), 7.12-7.17 (m, 3H), 7.32 (broad t, 1H), 7.38 (broad t, 2H), 7.47 (broad d, 2H), 7.88 (s, 1H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[C:6]([CH3:12])=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8]>CN1CCCC1.[Cu]>[CH3:12][C:6]1[C:5]([S:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8]
Reactant: C[S-]
Reactant: Cc1c(N)cccc1Br
Agent: [Cu]
Agent: CN1CCCC1
Agent: [Na+]
Product: CSc1cccc(N)c1C
Temperature: 0 °C

Procedure:
At 20° C., 4.3 g (61.81 mmol) of sodium thiomethoxide were added with stirring and ice-cooling to 10 g (53.75 mmol) of 3-bromo-2-methylaniline in 100 ml of N-methylpyrrolidine. After addition of 200 mg of copper powder, the reaction mixture was transferred into an autoclave and stirred at 240° C. for 16 h. The reaction solution was subsequently poured into 300 ml of ice-water and extracted 3× with methyl tert-butyl ether. The organic extracts were washed with water, dried and concentrated. The residue was chromatographed over silica gel using methylene chloride, giving 1.7 g (20.6% of theory) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([F:8])[N:3]=1.[Si:9]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[F:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:30]2[CH:29]=[CH:28][C:27]([O:26][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:32][CH:31]=2)[N:3]=1
Reactant: CC(C)(C)[Si](Oc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Reactant: Fc1cncc(Cl)n1
Product: CC(C)(C)[Si](Oc1ccc(-c2cncc(F)n2)cc1)(c1ccccc1)c1ccccc1
Yield: 69.5 %

Procedure:
In an analogous reaction to Example 1b, 8.86 g (66.85 mmol) of 2-chloro-6-fluoropyrazine (prepared as described in Example 1a) and 25.13 g (66.85 mmol) of 4-tert-butyldiphenylsilyloxyphenylboronic acid give 19.90 g of 2-fluoro-6-(4-tert-butyldiphenylsilyloxyphenyl)pyrazine. ##STR22## 4b
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:82][C@H:81]([CH2:83][O:84][C:85](=[O:87])[CH3:86])[C@@H:16]([O:17][C@@H:18]2[O:75][C@H:74]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[C@@H:29]([O:30][C@H:31]3[O:48][C@H:47]([CH2:49][O:50][C@H:51]4[O:68][C@H:67]([CH2:69][O:70][C:71](=[O:73])[CH3:72])[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:57]([O:58][C:59](=[O:61])[CH3:60])[C@H:52]4[O:53][C:54](=[O:56])[CH3:55])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]3[O:33][C:34](=[O:36])[CH3:35])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[Br:88]CCO.B(F)(F)F.CCOCC.C(OCC)(=O)C.C(CC(C)(C)C)(C)C>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C@H:18]2[O:75][C@H:74]([CH2:76][O:77][C:78](=[O:80])[CH3:79])[C@@H:29]([O:30][C@H:31]3[O:48][C@H:47]([CH2:49][O:50][C@H:51]4[O:68][C@H:67]([CH2:69][O:70][C:71](=[O:73])[CH3:72])[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:57]([O:58][C:59](=[O:61])[CH3:60])[C@H:52]4[O:53][C:54](=[O:56])[CH3:55])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]3[O:33][C:34](=[O:36])[CH3:35])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])[C@@H:81]([CH2:83][O:84][C:85](=[O:87])[CH3:86])[O:82][C@H:5]1[O:4][CH2:1][CH2:2][Br:88])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](O[C@H]4[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)O[C@@H]4COC(C)=O)O[C@@H]3COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCCBr
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](O[C@H]4[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]4COC(C)=O)O[C@@H]3COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Compound 92 (12.54 g, 9.85 mmol) and 2-bromoethanol (2.5 g, 1.4 ml, 20 mmol) were dissolved in dichloromethane (50 ml). Borontrifluoride etherate (7.1 g, 6.3 ml, 50 mmol) was added dropwise at room temperature and the mixture was stirred until the reaction was finished (48 h, TLC: SiO2, ethyl acetate:isooctane 3:1). The mixture was washed (water, saturated sodium hydrogen carbonate), dried (Na2SO4) and evaporated. The residue (12.3 g) was chromatographed (SiO2, ethyl acetate:isooctane 3:2) to give 93 (4.95 g, 63% based on transformed 92 and unreacted 92 (5.05 g). Compound 93 had [α]D25 +109° (c 1.3, chloroform). 1H-NMR (CDCl3, Me4Si) δ 5.35, 5.28, 5.18 (3d, each 1H, J=3.8, 2.8 and 3.6 Hz, H1', H1", H1"'), 4.60 (d, 1H, J=7.9 Hz, H1), 3.42-3.49 (m, 2H, CH2 -Br). 13C-NMR (CDCl3, TMS) δ 170.6-169.3 (CO), 100.4 (Cl), 95.9, 95.7, 95.3 (Cl', Cl", Cl"'), 77.3. 75.0, 73.7, 72.7, 72.2, 71.9, 71.8, 70.7, 70.4, 70.1, 69.9, 69.8, 69.7, 69.4, 69.3, 68.9, 68.5, 68.4, 67.4, 63.0, 61.8, 29.9, 21.1-20.6.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH:17]=[CH:21][CH:20]=[CH:19]3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)OC1CCc2c(N)cccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCc2c1cccc2-n1cccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
A stirred solution of 10.0 g (0.052 mole) of 4-amino-1-indanyl acetate (prepared as in Example 1, step F) and 7.5 g (0.056 mole) of 2,5-dimethoxytetrahydrofuran in 21.2 mL of acetic acid was heated under reflux for 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature, and was stirred for 16 hours. The reaction mixture was poured into 200 mL of chloroform. An aqueous saturated solution of sodium chloride (200 mL) was added, and the mixture was stirred for 10 minutes. The aqueous layer was separated and washed with 50 mL of chloroform. The combined organic phases were washed with two portions of 50 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 13.2 g of 4-(1-pyrrolyl)-1-indanyl acetate.
Reaction SMILES: [OH-].[Na+].O=C1[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[CH2:24][CH2:23]4)=[O:18])[CH2:12][CH2:11]2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[CH2:6][O:5]1>C(O)C>[OH:5][CH2:6][C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23]3)=[O:18])[CH2:12][CH2:11]1
Reactant: O=C(CN1CCC(N2C(=O)OCc3ccccc32)CC1)Nc1ccc2c(c1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CN1CCC(Nc2ccccc2CO)CC1)Nc1ccc2c(c1)CCC2=O
Temperature: 50 °C
Yield: 63.5 %

Procedure:
5 mL 10% sodium hydroxide were added to a suspension of 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-yl]-N-(1-oxo-indan-5-yl)-acetamide (25 mg, 0.06 mmols) in 5 mL ethanol. The resulting mixture was heated to 50° C. for 2 hours, cooled, the ethanol was evaporated and the aqueous phase was neutralized and extracted with methylene chloride (2×15 mL). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The crude material was purified via a silica gel column, eluting with ethyl acetate. 15 mg of a white solid were obtained, i.e. a yield of 64%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][O:20]C(=O)C)=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1.[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH2:28].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][OH:20])=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: CC(=O)OCCOc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2cc(OCCO)ccc21
Yield: 20 %

Procedure:
In accordance with general method O, 0.67 g (0.19 mmol) of acetic acid 2-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-ethyl ester, 0.26 g (0.0020 mol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.14 g of phosphine ligand and 0.70 g (7.3 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 20%; m.p.: 138° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].[Cl-].[NH4+]>CCOCC.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13]2)=[C:4]([F:11])[CH:3]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Br)cc2F)CCC1
Reaction time: 2.5 h
Yield: 59.1 %

Procedure:
A solution of (4-bromo-2-fluoro-phenyl)-acetonitrile (4.0 g, 18.7 mmol) from step 1 and 1,3-dibromopropane (2.1 mL, 20.6 mmol) in Et2O (5 mL) was slowly added to a slurry of NaH (1.64 g, 41.1 mmol, 60% in mineral oil) in DMSO (19 mL) at room temperature, being careful to keep the temperature below 35 degrees Celsius. The reaction was stirred for 2.5 hours, and then poured into 150 mL of saturated ammonium chloride. To this mixture was added CH22Cl2, and the layers were separated. The aqueous layer was extracted with 2×50 mL of CH2Cl2, and the organic layers were combined. After drying the liquid over MgSO4, the solids were filtered away, and the organic was concentrated to an oil. It was further purified by flash chromatography (90 g SiO2, 1:99->1:20 (EtOAc/Hexanes) to give the desired product (2.81 g, 59%). 1H NMR (400 MHz, CDCl3) δ: 2.06–2.16 (m, H), 2.51–2.63 (m, H), 2.66–2.76 (qd, J=9347 Hz, 2H), 2.86–2.94 (m, 2H), 7.16–7.22 (t, J=8.21 Hz, H), 7.30–7.41 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.C([OH:27])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@:21]([OH:27])([CH:22]=[CH2:23])[C@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH:10]=[CH:11][N:12]=2)[CH:8]=1
Reactant: CCO
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Product: C=C[C@@]1(O)CN2CC[C@@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reaction time: 72 h

Procedure:
A few drops of a suspension of M. plumbeus MMP 430 spores are added to 100 ml of medium A, described below, adjusted to pH7, in a 250 ml Erlenmeyer flask. Incubation is continued for 72 hours at 27° C. in a rotating agitator (327 RPM). A solution of 50 mg of quinidine in 1 ml of ethanol is then added under sterile conditions to the culture, and agitation is continued for 14 days under the same conditions. The culture is filtered on celite, the filtrate saturated with NaCl, brought to pH 10-12 by 2N NaOH, the extracted 6 times by methylene chloride. The dried and subsequently evaporated organic fractions are chromatographed on a preparative layer of silica gel, using as solvent CHCl2 -MeOH-NH4OH (85:14:1). The (3S)-3-hydroxy-quinidine band, identified by its fluorescence at 254 nm and its migration, which is smaller than that of quinidine, is scraped off and eluted by methanol. One obtains 1 mg of (3S)-3-hydroxy quinidine, identical with an authentic sample. Non-reacted quinidine is recovered in the same manner, and almost quantitatively (42 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.O.C(OCC)(=O)C>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4,5-Dichloro-2-fluoronitrobenzene (315 mg) was dissolved in dry dimethylformamide (10 ml) and diisopropylethylamine (0.85 ml), and 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (D40) (450 mg) were added at room temperature. The mixture was stirred at 80° C. for 1 h, then cooled to room temperature and water and ethyl acetate added. The organic layer was dried over MgSO4, filtered and evaporated to give the title compound, 350 mg.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[CH:23]=[C:15]2[CH2:16][N:17]([C:20](=[O:22])[CH3:21])[CH2:18][CH2:19][N:14]2[N:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[C:20]([N:17]1[CH2:18][CH2:19][N:14]2[N:13]=[C:12]([NH:11][C:2]3[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=3)[CH:23]=[C:15]2[CH2:16]1)(=[O:22])[CH3:21]
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(=O)N1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 98.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (481 mg, 1.8 mmol), 209b (270 mg, 1.5 mmol), 1,4-dioxane (20 mL), Pd2(dba)3 (137 mg, 0.15 mmol), XantPhos (173 mg, 0.30 mmol), and cesium carbonate (978 mg, 3.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 6 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 209c (540 mg, 89%) as a yellow solid. MS: [M+H]+368.0
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C
Yield: 53 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) was dissolved in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g), heated to 60° C. for 1 hour and then cooled to room temperature. To the above was added 3-(bromomethyl)tetrahydrofuran (0.103 g) and the reaction mixture heated at 50° C., overnight. The reaction mixture was quenched with water (25 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The combined organic phase was separated and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (97 mg).
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[N:11]=2)=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[N:11]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)Oc1ccc(Cc2nc(-c3c(F)cccc3Cl)nn2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 0.7 g of 5-(4-acetoxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of ethyl alcohol under ice-cooling, was added a solution of 0.62 g of potassium carbonate in 5 ml of water, and the reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was adjusted to pH 4 with diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.6 g of 5-(4-hydroxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.