Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].CCN(CC)CC.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([O:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OCCOCCOCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a CH2Cl2 (300 mL) solution of triethylene glycol (21 g, 140 mmol) was added Et3N (20 mL, 140 mmol); then trityl chloride (19.5 g, 70 mmol) in CH2Cl2 (100 mL) was added dropwise at 0° C. The mixture was stirred overnight and quenched with H2O. The organic phase was washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using hexane/EtOAc as the eluent to afford compound 21 (21 g, 53.6 mmol, 77% yield) as a clear liquid: 1H NMR (500 MHz, CDCl3) δ 7.47-7.46 (m, 6H), 7.28 (t, J=7.0 Hz, 6H), 7.21 (t, J=7.0 Hz, 3H), 3.68 (s, 8H), 3.60 (br, 2H), 3.25 (br, 2H), 2.57 (br, 1H); 13C NMR (126 MHz, CDCl3) δ 144.2, 128.8, 127.9, 127.1, 86.8, 72.7, 71.0, 70.8, 70.7, 63.4, 61.9; MS (ESI) m/z 415 (M+Na)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCC1(O)CCSCC1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Under a nitrogen atmosphere triethylamine (3.91 mL, 28.0 mmol) was added to a chilled (0° C.) solution of 2,4-dichloro-3-nitroquinoline (7.22 g, 26.7 mmol) in dichloromethane (100 mL). A solution of 4-(aminomethyl)tetrahydro-2H-thiopyran-4-ol (4.12 g, 28.0 mmol) in dichloromethane (30 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The orange residue was combined with saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (40 mL), sonicated for 10 minutes, and then filtered. The isolated solid was washed extensively with water and then dried to provide 5.63 g of 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-ol as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])([O-:3])=[O:2].Cl.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:22]([C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(=[O:33])[CH3:32]
Reactant: COC(=O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: Cl
Product: COC(=O)CCCN(C(C)=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
10 g of methyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-4-amino-n-butyrate (compound 2) are refluxed in 30 ml of acetyl chloride until the evolution of hydrogen chloride is complete. Excess acetyl chloride is removed in vacuo, affording the title compound in quantitative yield. nD21 =1.5437.
Reaction SMILES: [CH3:1][C:2]1([C:5](O)=O)[CH2:4][CH2:3]1.[NH2:8][NH:9][C:10]([NH2:12])=[S:11].P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]1([C:5]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CC1
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(c2nnc(N)s2)CC1

Procedure:
Commercially available, 1-methyl-cyclopropane-1-carboxylic acid (Aldrich), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-0.93 (m, 2H), 0.93-1.03 (m, 2H), 1.41 (s, 3H), 6.94 (s, 2H); MS (ESI+) m/z 156 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:6][C:3]=1[CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:33])C=1>C(OC(=O)C)C.C1CCCCC1>[Cl:1][C:2]12[O:33][C:3]1([CH:6]=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]2[Cl:10])[CH:4]=[CH2:5]
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(Cl)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=C(Cl)C1(Cl)O2
Yield: 99.6 %

Procedure:
Using the procedure of Stage D of Example 40, 13.2 g of thee allylic alcohol of Step C and 10.3 g of m-chloro perbenzoic acid were reacted to obtain 13.7 g of the expected product with a Rf=0.25 (AcOEt-cyclohexane 6-4).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.[C:37]1([N:43]2[C:47]3[CH:48]=[CH:49][C:50](B(O)O)=[CH:51][C:46]=3[N:45]=[C:44]2[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:37]1([N:43]2[C:47]3[CH:48]=[CH:49][C:50]([C:2]4[CH:15]=[CH:14][C:13]5[C:4](=[C:5]([C:27]6[CH:36]=[CH:35][C:34]7[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=7)[CH:28]=6)[C:6]6[C:11]([C:12]=5[C:16]5[CH:25]=[CH:24][C:23]7[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=7)[CH:17]=5)=[CH:10][C:9]([C:50]5[CH:49]=[CH:48][C:47]7[N:43]([C:37]8[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=8)[C:44]([C:55]8[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=8)=[N:45][C:46]=7[CH:51]=5)=[CH:8][CH:7]=6)[CH:3]=4)=[CH:51][C:46]=3[N:45]=[C:44]2[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OB(O)c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3cc(Br)ccc3c(-c3ccc4ccccc4c3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc3cc(-c4ccc5c(-c6ccc7ccccc7c6)c6cc(-c7ccc8c(c7)nc(-c7ccccc7)n8-c7ccccc7)ccc6c(-c6ccc7ccccc7c6)c5c4)ccc3n2-c2ccccc2)cc1
Yield: 73 %

Procedure:
2.0 g (3.4 mmol) of 2,6-dibromo-9,10-di(2-naphthyl)anthracene, 2.4 g (7.5 mmol) of 1,2-diphenyl-1H-benzimidazole-5-boronic acid, and 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 30 mL of 1,2-dimethoxyethane. Then, 15 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. The resultant was stood to cool. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 2.4 g of a greenish white crystal (73% yield). Mass spectral analysis confirmed that the crystal was a target product. The crystal had an m/e of 966 with respect to a molecular weight of 966.37.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)[CH2:6][CH2:5]2.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]([OH:13])[CH2:16][OH:15])[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H](C2CCc3cc(F)ccc3O2)O1
Solvent: CC(=O)O
Solvent: O
Product: OC[C@@H](O)C1CCc2cc(F)ccc2O1
Temperature: 65 °C
Yield: 89 %

Procedure:
6-Fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (40 mg, 0.16 mmol, diastereomeric ratio 75:25) was dissolved in acetic acid (2 ml) and demi water (0.7 ml). The reaction mixture was stirred vigorously and heated to 65° C. After 3 h at 65° C. the reaction mixture was cooled to 25° C. The solution was then concentrated in vacuo at 35° C. to obtain (R)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethane-1,2-diol as a vetrous oil (89% yield, diastereomeric ratio 73:27).
Reaction SMILES: [F-].[K+].[C:3]1([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.Cl>CN(C=O)C>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:18][CH2:17]3)=[N:22][CH:23]=1)([O-:29])=[O:28]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 120 °C

Procedure:
Potassium fluoride (225 mg) was added into a solution of 2-phenylchroman-6-ol (300 mg) in dry DMF (3 ml). After stirring the resulting mixture at 120° C. for 30 minutes 2-chloro-5-nitropyridine (195 mg) was added. The reaction mixture was stirred for a further 6½ hours at 120° C. After cooling into room temperature 1 M HCl-solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water then with saturated NaCl-solution and dried with Na2SO4. 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine was recrystallised from acetone-2-propanol (1:5). 1H NMR (400 MHz, d6-DMSO) δ: 9.00 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.47-7.32 (m, 5H), 7.20 (d, 1H, J 9.2 Hz), 7.00-6.89 (m, 3H), 5.15 (dd, 1H, J 10.1, 2.2 Hz), 2.99 (ddd, 1H, J −16.8, 11.3, 6.2 Hz), 2.75 (ddd, 1H, J −16.8, 5.4, 3.3 Hz), 2.18 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1N.N([O-])=O.[Na+].[ClH:17]>O.Cl[Cu]>[Cl:17][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: Cl
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of 15.5 g (92.26 mmol) 2-methoxy-6-nitro-phenylamine, 31 ml water and 31 ml conc. HCl, a solution of 6.36 g (92.26 mmol) NaNO2 in 38 ml water is slowly added dropwise at −10° C.-0° C. After stirring for 0.5 h the mixture is slowly added to a solution of 11.88 g (120 mmol) CuCl in 93 ml conc. HCl. After completion of the addition stirring is continued for 1.5 h at room temperature and for 0.5 h at reflux temperature. The reaction mixture is allowed to cool to room temperature and is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 12.69 of the title compound as a crystalline solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH:16]=[N:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][C:5]=3[NH:6][C:7]=2[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.B1([O-])O[O:23]1.O.O.O.O.[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:3]2[C:4]3[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=3[NH:6][C:7]=2[C:8]([C:11](=[O:23])[NH2:12])=[CH:9][CH:10]=1
Reactant: [O-]B1OO1
Reactant: CCOC(=O)c1cc2[nH]c3c(C#N)ccc(Br)c3c2cn1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(=O)O)ncc12
Temperature: 100 °C
Yield: 79.2 %

Procedure:
A suspension of crude ethyl 9-bromo-6-cyano-5H-pyrido[4,3-b]indole-3-carboxylate (0.78 g, 2.266 mmol) and sodium perborate tetrahydrate (1.395 g, 9.07 mmol) in ethanol-water (3:2, 99 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature and the ethanol was removed under vacuum to give a suspension. The pH was adjusted to about 5-6 with 1 M aqueous HCl. The precipitate was collected by filtration, washed with water and air-dried to afford the desired product (0.60 g). The filtrate was concentrated under vacuum to provide additional desired product (70 mg, total of 88% yield). LCMS (M+H)+ m/z 334.0, 335.9.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[NH:20][CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[N:20]([CH2:2][CH2:3][OH:4])[CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1
Reactant: OCCBr
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(CCO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 by reaction of 2-bromoethanol with compound 9F. 1H NMR (400 MHz, MeOD) δ ppm 1.70 (s, 3H) 3.74 (s, 3H) 3.82 (t, J=5.05 Hz, 2H) 4.13 (t, J=5.05 Hz, 2H) 4.53 (s, 1H) 6.78 (t, J=8.72 Hz, 1H) 7.26 (dd, J=8.21, 1.39 Hz, 1H) 7.37 (dd, J=10.48, 2.15 Hz, 1H) 10.27 (s, 1H) [M+H] calc'd for C17H16BrFN4O3, 424; found, 424.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[Se](=O)=[O:16].O1CCOCC1.O>O>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH:1]=[O:16])[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 90 °C

Procedure:
2-Methyl-6-nitroquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide 90.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 6-nitro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 6-nitro-2-quinolinecarboxaldehyde prepared above in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M solution in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h, the mixture was treated with water (0.2 ml) and loaded onto an IBSIL-C87 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product was eluted with methanol. Evaporation of the methanol gave compound 282 as a pale yellow solid.
Reaction SMILES: [CH3:1]C1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[C:40]([OH:50])(=[O:49])[C@H:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42]>>[CH3:1][O:49][C:40](=[O:50])[C@@H:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: COC(=O)[C@H](O)c1ccccc1

Procedure:
The transformed strain XL10-Gold (pTrcFadLPL) prepared in Example 3 was inoculated again in 250 mL Erlenmeyer flask including 100 mL of LB liquid medium containing 50 μg/L of ampicillin, and then cultured at 37° C. Gene expression was induced by adding 0.1 mM of IPTG, when absorbance was 0.5 at 600 nm wavelength by spectrophotometer. 5 hours after inducing the expression, culture broth was centrifuged at 4° C., 600 rpm for 5 minutes to collect cells, and then, the collected cells were washed with 50 mM Tris-HCl solution (pH 8.0), followed by resuspending in 3 mL of buffer. Said re-suspension was put into a 10 mL flask, to which 30 mg of racemic mandelic acid methyl ester was added and allowed to react for 48 hours with stirring. Then, the suspension was centrifuged at 4° C. and 6000 rpm for 5 minutes to remove cells. The supernatant was collected and adjusted to a pH of 3.0. After extraction of the supernatant with 10 mL of ethyl acetate and hexane, the extract was analyzed by liquid chromatography. The analysis results showed that (S)-mandelic acid and (R)-mandelic acid methyl ester were obtained.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16](/[C:19](/[CH3:23])=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:26]([O:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](/[C:19](/[CH3:23])=[CH:20]/[CH2:21][O:22][C:39]3[CH:38]=[CH:37][C:36]([CH2:35][C@H:29]([O:28][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=3)=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C/C(=C\CO)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)cc1)OCC
Yield: 81.3 %

Procedure:
The title compound (656 mg, 81%) was prepared as a colourless oil from (E)-3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-en-1-ol (500 mg, 1.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (348 mg, 1.46 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.[Au](Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:16]([CH3:17])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)CCCOCc1ccccc1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc(CCCOCc2ccccc2)o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of 4-Benzyloxy-N-prop-2-ynyl-butyramide (500 mg, 2.16 mmol) in acetonitrile (22 ml) was treated with Gold (III) chloride (32.8 mg, 0.108 mmol) at room temperature. The reaction was heated at 50° C. for 8 hours then was allowed to stir at room temperature overnight. The reaction was concentrated under reduced pressure and the residue was purified on silica gel using 1:1/heptane:ethyl acetate as eluant. Fractions that contained product were combined and concentrated under reduced pressure to yield 2-(3-Benzyloxy-propyl)-5-methyl-oxazole (405 mg, 81%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]1[N:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13](NC1C=CC=CC=1C)=[O:14]>>[F:10][C:11]1[N:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1cccnc1F
Yield: 100 %

Procedure:
4-Fluorobenzylamine (Aldrich, 0.18 mL, 1.6 mmol) was converted to the desired compound (0.099 g, 100%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). MS(ESI+) m/z 249 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:27]3[C:22](=[CH:23][N:24]=[CH:25][CH:26]=3)[C:18]3([CH2:21][O:20][CH2:19]3)[O:17][C:15]=2[CH:16]=1)(C)(C)C.[ClH:33].C(OCC)C>ClCCl>[NH2:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:27]3[C:22](=[CH:23][N:24]=[CH:25][CH:26]=3)[C:18]([CH2:21][OH:20])([CH2:19][Cl:33])[O:17][C:15]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC1(COC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Reactant: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(CO)(CCl)c1cnccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of ((S)-tert-butyl(4-methyl-1-(spiro[chromeno[3,4-c]pyridine-5,3′-oxetan]-8-yloxy)pentan-2-yl)carbamate (10 mg, 0.023 mmol) (prepared as described in Example 19, Part D) in dichloromethane (1 mL) cooled to 0° C. was added 1M HCl in diethyl ether (23 μL, 0.023 mmol) dropwise and the solution stirred for 30 min. The reaction was then warmed to room temperature and stirred for 2 h. After completion of reaction, the volatiles were removed under reduced and purified by preparative HPLC to afford product (8-(((S)-2-amino-4-methylpentyl)oxy)-5-(chloromethyl)-5H-chromeno[3,4-c]pyridin-5-yl)methanol (2.08 mg, 5.52 μmol, 24% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.82 (m, 1H), 8.69 (m, 1H), 8.35 (m, 1H), 8.09 (m, 1H), 6.94 (m, 1H), 6.82 (s, 1H), 4.36-4.20 (m, 6H), 3.73 (m, 1H), 1.82-1.68 (m, 3H), 1.04 (m, 6H); LCMS (ESI) m/e 377.2 [(M+H)+, calcd for C20H26ClN2O3 377.2]; LC/MS retention time (Method E): tR=1.71 min; HPLC retention time (method A): tR=8.12 min; HPLC retention time (method B): tR=9.87 min.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (1.0 ml), and 3,5-dichlorobenzoyl chloride (1.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:12][C:13]([NH2:15])=[NH:14].C(N(CC)CC)C>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:12]=[C:13]([NH2:15])[N:14]=[CH:7][C:6]=2[CH:9]=1
Reactant: N=C(N)N
Reactant: O=Cc1cc(Br)cnc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-bromo-2-fluoronicotinaldehyde (3.0 g, 14.78 mmol), guanidine hydrochloride (1.69 g, 17.74 mmol) and triethylamine (4.48 g, 44.35 mmol) were dissolved in 1-methyl-2-pyrrolidinone (15 mL), and the reaction mixture was stirred at 180° C. for 15 min under microwave. The mixture was cooled to RT, quenched with water (200 mL) and extracted with ethyl acetate (2×300 mL). The organic layers were combined, washed with water (3×50 mL) and brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=3:1) to afford 6-bromopyrido[2,3-d]pyrimidin-2-amine (2.0 g, 60%) as a yellow solid. MS (ES+) C7H5BrN4 requires: 224, 226. Found: 225, 227 [M+H]+.