Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:36].IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@@H:10]([CH3:36])[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of (S)-1-t-butoxycarbonyl-5-t-butyldiphenylsiloxymethyl-pyrrolidine-2-one (15 g, 33 mmol) in THF (250 mL) at -78° C. a 1M solution of LiN(SiMe3)2 (35 mL, 35 mmol) was slowly added. After stirring for 1 hr, iodomethane (6.2 mL, 100 mmol) was added. The reaction mixture was allowed to stir for another 2 hr at -78° C. and then quenched with acetic acid. The mixture was concentrated into half volume, diluted with water (200 mL) and extracted with ethyl acetate (EtOAc). The combined extracts were washed with water, brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue purified by flash column chromatography on silica gel, eluted with EtOAc:Hexane (1:2.5). The desired (2S,5R) isomer was eluted first from the column and crystallized in hexanes to give 7.3 g (47%) of product as white crystals. mp=84°-85° C. 1H NMR (200 MHz, CDCl3): δ 7.62 (m, 5H), 7.40 (m, 5H), 4.12 (m, 1H), 3.85 (dd, J=10.3, 4.7 Hz, 1H), 3.72 (dd, J=10.3, 2.8 Hz, 1H), 2.82 (m, 1H), 2.31 (dd, J=12.7, 8.9 Hz, 1H), 1.75 (m, 1H), 1.42 (s, 9H), 1.20 (d, J=7.0 Hz, 3H), 1.02 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]4[CH2:24][O:23]4)=[CH:15][CH:16]=3)[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(N(C(C)C)CC)(C)C>C(O)C>[OH:23][CH:22]([CH2:24][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:35])([F:36])[F:25])[CH:28]=1)[CH2:21][O:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][O:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2coc3cc(OCC(O)CNCc4cccc(C(F)(F)F)c4)ccc3c2=O)cc1

Procedure:
3-(4-Methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol), 3-(trifluoromethyl)benzylamine (0.11 ml, 0.74 mmol) and diisopropylethylamine (0.26 g, 1.47 mmol) was stirred in ethanol (15 ml) at 78° C. overnight. The solvent was removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 5% methanol/dichloromethane, followed by recrystallization from ethyl acetate/hexane to provide 7-[2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propoxy]-3-(4-methoxyphenyl)chromen-4-one.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O>[N+:1]([C:7]1[CH:6]=[C:5]([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[C:16]([F:17])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1nncn1-c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(-n2cnnc2C(F)(F)F)c1
Yield: 63.9 %

Procedure:
Fuming nitric acid (0.5 g) was added to 4-phenyl-3-trifluoromethyl-1,2,4-triazole (1.06 g) (see Example 1) in concentrated sulphuric acid (15 ml) at 5°-10° and then slowly heated to 85° for 1 hr. The cooled acid solution was poured onto ice to give 4-(3-nitrophenyl)-3-trifluoromethyl-1,2,4-triazole (0.82 g, 63.4%) m.p. 142° (from benzene). Found: C, 41.70%; H, 2.13%; F, 22.1%; N, 21.43%. C9H5F3N4O2 requires: C, 41.87%; H, 1.95%; F,22.1%; N, 21.70%). High resolution nmr spectroscopy indicated substitution in the m-position of the phenyl ring. m/e, 259.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:6]([C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:19][C:14]=2[CH:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2nc3cc(C)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
4-Methylbenzoyl chloride (2.17 mL, 2.54 g, 16.4 mmol) in dichloromethane (25 mL) was added dropwise to a stirred, cooled (0° C.) solution of 4-methyl-1,2-benzenediamine (2.0 g, 16.4 mmol) and triethylamine (4.57 mL, 3.32 g, 33 mmol) in dichloromethane (25 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, acetic acid (40 mL) was added and the mixture was stirred at 100° C. for 24 h. The solvent was evaporated under reduced pressure, water (100 mL) was added and the pH was adjusted to 7.0 with aqueous sodium carbonate (10%). Ethyl acetate (50 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (4×35 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, heated to reflux and allowed to cool. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (1.17 g, 32%). 1H NMR (360 MHz, CDCl3) δ 7.92 (2H, d, J 8.2 Hz), 7.52 (1H, d, J 8.1 Hz), 7.38 (1H, d, J 1.0 Hz), 7.27 (2H, d, J 8.2 Hz), 7.08 (1H, dd, J 8.1, 1.0 Hz), 2.47 (3H, s), and 2.40 (3H, s). m/z (ES+) 223 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[C:2]([N:1]2[CH:12]=[CH:16][CH:15]=[CH:14]2)=[C:3]([OH:9])[CH:4]=[CH:5][CH:6]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1cccc(O)c1N
Solvent: CC(=O)O
Product: Cc1cccc(O)c1-n1cccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
A round bottom flask was charged with 2-amino-3-methyl-phenol (2.5 g, 20.3 mmol) and acetic acid (37.5 mL) which provided a very dark solution. Stirring was commenced and the vessel was charged with 2,5-dimethoxytetrahydrofuran (2.6 mL, 20.3 mmol) added neat dropwise over a period of 2 minutes. The dark mixture was then heated at 100° C. for 3 h then 80° C. for 12 hours. The solvent was evaporated under vacuum and the crude residue purified by column chromatography using a gradient of 0.5-50% EtOAc in hexanes to yield 3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 83%). ESI-MS m/z calc. 173.1, found 174.3 (M+1)+. Retention time: 1.31 minutes (3 min run).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[CH:7]=[CH2:8]>CO>[CH2:6]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH2:13][CH2:14]1)[CH:7]=[CH2:8]
Reactant: C=CCN1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: C=CCN1CCN(c2ncc(N)cn2)CC1

Procedure:
3.84 g (17.0 mmol) of tin(II) chloride dihydrate were added to a solution of 530 mg (2.13 mmol) of 2-(4-allylpiperazin-1-yl)-5-nitropyrimidine from Example 16.1 in 20 ml of methanol and, after that, the reaction mixture was heated at reflux for 1 hour. After the solvent had been evaporated to dryness, the residue was treated with saturated aqueous sodium chloride solution and then made alkaline using dilute aqueous sodium hydroxide solution. After that, the aqueous reaction mixture was extracted with ethyl acetate. The solid which had precipitated out was filtered off with suction. The phases were then separated and the aqueous phase was extracted in each case twice with ethyl acetate and dichloromethane. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, 220 mg (46% of theory) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:17][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nn2cccc(Br)c2c1-c1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nn2cccc(Br)c2c1-c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-phenyl-pyrazolo[1,5-a]pyridin-2-ylamine (0.295 g 1 eq) was dissolved in DCM (3 mL) at 5° C. and Et3N (356 μL) was added followed by the cyclopropane carbonyl chloride (234 μL). The reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo the residue was treated with 7 M methanolic ammonia solution (5 mL) and stirred at room temp for 1 h to hydrolyse any bis-acylated product. The solvent was removed in vacuo and the residue was re-dissolved in DCM and washed with water and brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=[N:31]1.NN1CCCCC1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([NH:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 86.4 %

Procedure:
2,4-bis-benzyloxy-5-isopropylbenzoic acid (F67-01: 188 mg, 0.5 mmol), dimethylformamide (2 mL) and 1-hydroxy-1,2,3-benzotriazole (72 mg, 0.55 mmol) were placed in a test tube and then 1-amino-piperidine (0.059 mL, 0.55 mmol) was added. A mixed solution of dimethylformamide (1 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and triethylamine (0.15 mL, 1.1 mmol) was slowly added to the reaction mixture at 0° C. while stirring. Further, the reaction mixture was allowed to come to room temperature and stirred for 24 hours. After completing the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was washed 4 times with saturated sodium chloride, dried with sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol) followed by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (F67-02: 198 mg, 86.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[NH:9]C(=O)C.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:25](OCCC(C)C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:25][NH:9][C:3]=12
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1c(Br)ccnc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Brc1ccnc2cn[nH]c12
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a solution of N-(4-bromo-2-methylpyridin-3-yl)acetamide (0.6 g, 2.62 mmol) in toluene (26.2 ml) was added potassium acetate (0.308 g, 3.14 mmol) and acetic anhydride (0.743 ml, 7.86 mmol). The mixture was stirred for 15 minutes and isopentyl nitrite (0.806 ml, 6.02 mmol) was added and the reaction was heated at 85° C. for 4 hours. The reaction was cooled and partitioned between ethyl acetate (75 mL) and water (75 mL). The organic layer was separated, dried over MgSO4, and concentrated to a brown oil. The oil was purified on silica column chromatography eluted with methanol:dichloromethane (3:97). Concentration of product fractions afforded 7-bromo-1H-pyrazolo[4,3-b]pyridine (90 mg, 0.454 mmol, 17.35% yield) as an amber solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (1H, d, J=4.80 Hz) 8.32-8.40 (1H, m) 8.40-8.51 (1H, m) 13.89 (1H, br. s.). MS [M+H] found 197.9.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)[N:4]2[C@H]1C(O)=O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:49][C@@H:50]2[O:55][C@@H:54]([CH2:56]O)[C@H:53](O)[C@@H:52](O)[C@@H:51]2[NH:60]C)[C@@]1(O)C=O.C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[Na+]>OCC(CO)O>[NH2:60][C@H:51]([C:50]([OH:55])=[O:49])[CH2:52][CH2:53][CH2:54][CH2:56][NH2:4]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
Glycerol stocks of the strains obtained in Example 3, in which fad genes were amplified, were thawed. And, 100 μL of each was evenly spread on an LB agar medium plate containing 50 mg/L ampicillin and 20 mg/L streptomycin and incubated at 37° C. for 24 hours. About ½ volume of bacterial cells on the obtained plate were inoculated into 5 mL of fermentation medium described below containing 50 mg/L ampicillin and 20 mg/L streptomycin in a test tube manufactured by AGC TECHNO GLASS CO., LTD. (diameter×length×thickness (mm)=25×200×1.2), and cultured using a reciprocal shaking culture apparatus at 37° C. for 72 hours. As a carbon source in a main culture, sodium oleate added with polyoxyethylene sorbitan monooleic acid ester (Tween 80: manufactured by NACALAI TESQUE, INC.) as an emulsification promoter to a final concentration of 0.5% (w/v) was used. As for a total amount of carbon sources, sodium oleate was 10 g/L. The medium composition used for the culture is shown below.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29](O)(=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(CC(C)(C)C)(C)C>CCOCC>[CH3:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]/[CH:38]=[CH:37]\[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:19][C@@H:18]1[CH2:17][C:16]2[C@@:22]([CH3:23])([C@@H:24]3[C@@H:13]([CH2:14][CH:15]=2)[C@@H:12]2[CH2:11][CH2:10][C@H:9]([C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[C@@:27]2([CH3:28])[CH2:26][CH2:25]3)[CH2:21][CH2:20]1)=[O:47]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOCC
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 18 h

Procedure:
A mixture of 10 g of cholesterol, 22 g of oleic acid, 50 ml of isooctane and 200 ml (50,000 U) of an aqueous solution of lipase MY was stirred at 200 rpm for 18 hours. Thereafter, ether was added and the mixture was washed with aqueous sodium bicarbonate to remove the aqueous layer. After several repetitions of this procedure, the ether layer was dried on anhydrous sodium sulfate. The ether was then distilled off to give cholesteryl oleate, which was a white semi-transparent crude product, in 96.3% purity and in a yield of 16.0 g (95.0%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C#N)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo-2-fluoro-benzonitrile (270 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (336 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J=8.84, 7.33 Hz, 1 H) 7.28 (s, 1 H) 7.24 (d, J=1.26 Hz, 1 H) 6.81 (dd, J=8.34, 2.02 Hz, 1 H) 6.75 (dd, J=10.23, 2.40 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C19H16FNO4 m/z 342.00 (M+H+).
Reaction SMILES: O[CH2:2][C@@:3]([C@@H:6]1[CH2:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH3:26])=[CH:14][CH:13]=2)=[C:9]([CH3:28])[CH2:8][CH2:7]1)([OH:5])C.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)C.O>[CH3:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH2:11][C@H:6]([C:3](=[O:5])[CH3:2])[CH2:7][CH2:8][C:9]=2[CH3:28])=[CH:17][CH:16]=1)=[O:27]
Reactant: CC1=C(c2ccc(NC(=O)c3ccncc3C)cc2)C[C@@H]([C@@](C)(O)CO)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)[C@@H]1CCC(C)=C(c2ccc(NC(=O)c3ccncc3C)cc2)C1
Temperature: 25 °C

Procedure:
A solution of Compound 9 was dissolved in 2:1 isopropyl alcohol and water and stirred at room temp. Sodium periodate (1 eq.) was added and the reaction was stirred overnight, quenched with water and washed with ethyl acetate. The organic layer was dried and concentrated to yield 38.0 mg Compound 6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Br[C:12]1[CH:17]=[C:16](F)C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: Oc1c(F)cc(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Product: C=CC[C@H](C)Oc1c(F)cc(F)cc1Br
Yield: 92 %

Procedure:
Prepared in 92% yield from 2-bromo-4,6-difluorophenol following the procedure for (S)-1-bromo-4,5-difluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.19-7.06 (m, 1H), 6.85 (ddd, J=10.9, 8.2, 3.0 Hz, 1H), 5.90 (ddt, J=17.2, 10.1, 7.0 Hz, 1H), 5.19-5.07 (m, 2H), 4.46-4.30 (m, 1H), 2.65-2.48 (m, 1H), 2.48-2.39 (m, 1H), 1.31 (dd, J=6.1, 0.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)Cl.C(O)(=O)C>[Br:20][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: BrBr
Reactant: Fc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1

Procedure:
A solution of 2,3-bis(4-fluorophenyl)thiophene (272 mg, 1 mmole) in 3 ml methylene chloride was diluted with 3 ml glacial acetic acid and cooled to 10°. A solution of 0.5 M bromine in acetic acid (1.1 ml) was added. After 21/2 hours an additional portion of bromine in acetic acid (1.1 ml) was added. After a total rection time of 51/2 hours, the reaction mixture was concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[O:6][CH2:5][CH2:4][O:3]1.[O-2].[Ca+2].S1C=CC=C1>O1CCCC1.[Pt]>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccccc2[N+](=O)[O-])OCCO1
Agent: [Pt]
Agent: [Ca+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CC1(c2ccccc2N)OCCO1
Yield: 78.2 %

Procedure:
2-methyl-2-(2-nitrophenyl)- 1,3-dioxolane (0.132 mol) was dissolved in tetrahydrofuran (600 ml) and this solution was hydrogenated with platinum on activated carbon (4 g) as a catalyst in the presence of calcium oxide (10 g) and thiophene (3 ml). After uptake of H2 (3 equiv), the catalyst was filtered on celite and washed with tetrahydrofuran. The flitrate was evaporated. The residue was recrystallized from n-hexane. The crystals were filtered off and dried, yielding 18.5g (78%) of 2-(2-methyl-1,3-dioxolan-2-yl)benzenamine (interm. 27).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[CH:28]=[C:29]2[C:35]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])=[N:34][O:33][C:30]2=[N:31][CH:32]=1.C([Sn](CCCC)(CCCC)[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)CCC>CN(C=O)C>[S:56]1[CH:57]=[C:53]([C:27]2[CH:28]=[C:29]3[C:35]([CH:36]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[CH:43][CH:42]=[CH:41]5)[CH3:37])=[N:34][O:33][C:30]3=[N:31][CH:32]=2)[N:54]=[CH:55]1
Reactant: CC(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: CC(c1ccc2ncccc2c1)c1noc2ncc(-c3cscn3)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), and 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to afford the product as an off-white solid. MS m/z=359.0 [M+1]+ Calc'd for C20H14N4OS: 358.4.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH2:19][CH2:20][OH:21])[N:17]=[CH:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:21][CH2:20][CH2:19][N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:15][CH:16]=[N:17]1
Reactant: OCCn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCO)nc2-3)cn1

Procedure:
Following the procedure for 114, 2-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-ethanol was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 442. MS (ESI+) 453.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.42 (dd, J=8.3, 1.8, 1H), 7.30 (d, J=1.7, 1H), 4.94 (t, J=5.5, 1H), 4.89 (t, J=5.9, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0, 2H), 4.04 (s, 2H), 3.91 (q, J=5.8, 2H), 3.44 (t, J=5.0, 2H), 1.10 (s, 6H)