Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl.[O:19]([NH2:21])[CH3:20]>O>[CH3:20][O:19][N:21]=[CH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: CON
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
An amount of 1H-Indole-6-carbaldehyde (50 mg, 0.34 mmol) is added to pyridine (2.0 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (31.6 mg, 0.38 mmol). The mixture is stirred at ambient temperature for 24 h, and 10 mL of water is added. After the solvents were evaporated, the residue is dissolved 10 mL of anhydrous ether, washed successively with 10 mL of aqueous sodium bicarbonate, 10 mL of sodium bisulfite, and 10 mL of brine. Dried over magnesium sulfate, evaporated to give a white solid (49 mg, 0.281 mmol). MS (ESI) m/z 176.3 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[ClH:28].[CH2:29](O)[CH3:30]>>[ClH:28].[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([O:24][CH2:29][CH3:30])=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCC
Reaction time: 8 h

Procedure:
A solution of 3.0 g of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline in 50 ml of absolute ethanol is saturated with HCl gas at 0°. After standing at 0° overnight, the HCl and ethanol are removed under vacuum to afford 3.1 g of an oil which upon freeze-drying gives a white solid. Thin layer chromatography and HPLC indicate only one component. The nmr spectrum indicates two ethyl groups per aromatic ring. The mass spectrum shows a molecular ion at 404 m/e.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([CH:28]=[C:29]([F:32])[C:30]=4[CH3:31])[C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[C:12](=[O:33])[N:11]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[CH:10]=2)[CH2:4][CH2:3]1.[CH3:38][C:39]([CH3:41])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[C:29]([F:32])[C:30]([CH3:31])=[C:19]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[C:12](=[O:33])[N:11]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[CH:10]=[C:9]4[CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH:39]([CH3:41])[CH3:38])[CH2:3][CH2:4]3)[CH:20]=2)[CH2:26][CH2:27]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(N)CC3)c2c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(NC(C)C)CC3)c2c1
Reaction time: 0.08 h

Procedure:
The product of Example 83 (50 mg) was dissolved in dichloromethane (10 mL) and acetone (0.037 mL) added. The solution was stirred for 5 minutes then sodium triacetoxyborohydride (63.3 mg) added. The mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure and the residue purified by HPLC to give the title compound as a solid (45 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48]([C:50]1(Br)[CH2:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:50]3([C:48]([O:47][CH2:45][CH3:46])=[O:49])[CH2:53][CH2:52][CH2:51]3)[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 1.5 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 1.8 g of cesium carbonate and 1.2 g of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:16]=3[S:15](=[O:25])(=[O:24])[CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:27][CH2:28][CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:27][CH2:28][CH2:29][OH:30])=[CH:22][C:16]=3[S:15](=[O:25])(=[O:24])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3ccccc3n2)Cc2ccc(O)cc21
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(c2cc(Cl)c3ccccc3n2)Cc2ccc(OCCCO)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A mixture of 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol 1,1-dioxide (374.0 mg, 1.0 mmol), 3-bromo-propan-1-ol (0.37 mL, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in N,N-dimethylformamide (1.5 mL) was heated with stirring at 70° C. for 2 hours. After being cooled to room temperature, the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined organic layers were washed with water (50 mL×2) and a saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 421.6 mg of the crude product as a yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 433.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[N:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=3)[CH2:9][C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(=O)(O)[O-].[Na+].O>COCCOCCOC>[CH:1]1[C:6]2[C:7]3[N:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=3)[CH2:9][C:10](=[S:21])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Temperature: 100 °C
Yield: 767.4 %

Procedure:
A mixture of 15 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 3.09 g phosphorus pentasulfide and 11.46 g sodium bicarbonate in 300 ml diglyme was heated at 100° C. for two hours. The resulting mixture was cooled and poured into 3 L water to precipitate a solid. The solid was collected, triturated successively with cyclohexane, ether and hexane and dried (P2O5) to give 14.1 g solid. Recrystallization of 4.0 g from n-propanol gave 3.0 g solid, m.p. 259°-261° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][CH:39]([OH:41])[CH3:40]>>[CH:39]([O:41][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1)([CH3:40])[CH3:38]
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OC(C)C)c5ccccc45)cc3)ccnc2c1

Procedure:
In a 5 mL sealed tube, was dissolved 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (0.100 g, 0.224 mmol) in iPrOH (0.500 mL). To this was added cesium carbonate (0.110 g, 0.336 mmol) and the mixture was irradiated for 30 min at 140° C. in the microwave. When the reaction was determined to be complete by LC/MS, it was concentrated. The mixture concentrate was purified using Isco silica gel chromatography, using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2, followed by reverse phase chromatography (Gilson, 10-90% TFA/acetonitrile in water over 15 min). The product-containing fractions were extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through fritted funnel, and concentrated to yield 4-isopropoxy-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS [M+H]+=470.0; Calc'd=469.6 for C26H23N5O2S
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9](C1C(C)=NNC=1C)[NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[NH:10]
Reactant: Cc1n[nH]c(C)c1C(N)=NC(=O)OC(C)(C)C
Reactant: NCCCN
Product: CC(C)(C)OC(=O)NC(=N)NCCCN
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.2 %

Procedure:
A mixture of tert-butoxycarbonyl-1-(3,5-dimethylpyrazolyl)-formamidine (0.38 g, 1.5 mmol) and 1,3-diaminopropane (0.56 g, 7.5 mmol) was stirred at room temperature for 17 h. The crystalline product was collected by filtration, washed with toluene (2×0.7) mL), and vacuum dried (35° C., 1.5 h) to afford 0.15 g (47%) of white crystals of N-(3-aminopropyl)-N'-tert-butoxycarbonyl guanidine (IIIg).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[C:24]([O:38][CH3:39])[CH:23]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=[C:8]2[N:7]=1)C.[OH-].[K+]>C(O)CO.O>[CH3:39][O:38][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH2:21][N:20]1[C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=[C:8]2[N:7]=[C:6]1[NH2:5]
Reactant: CCOC(=O)Nc1nc2cc(-c3ccccc3)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccc5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a stirred solution of ethyl(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.090 g, 0.17 mmol) in ethylene glycol (10 mL) and water (10 mL) was added potassium hydroxide (1.00 g, 17.82 mmol). The mixture was heated to 100° C. After 48 h, the mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to afford 0.027 g (34%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.70-7.68 (m, 3H), 7.50 (s, 2H), 7.40 (s, 1H), 6.90-6.77 (m, 4H), 5.31 (s, 2H), 5.05 (s, 2H), 4.77 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H) ppm; (M+1)=468.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[O:9][C:8](=[O:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH:4]1[O:9][C:8](=[O:10])[CH:7]=[C:6]([OH:11])[CH2:5]1
Reactant: [H][H]
Reactant: COC(OC)c1cc(O)cc(=O)o1
Agent: [Pd]
Solvent: CO
Product: COC(OC)C1CC(O)=CC(=O)O1

Procedure:
6-Dimethoxymethyl-4-hydroxypyran-2-one may be reduced in methanol with hydrogen in the presence of a palladium on carbon catalyst to give 6-dimethoxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one;
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:27])=[O:24]
Reactant: COC(=O)Cc1cccc(OCC(C)=O)c1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1cccc(OCC(C)NCC(O)c2cccc(Cl)c2)c1
Yield: 58.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.11 g of methyl 3-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 17), 70 ml of benzene, 60 ml of absolute methanol and 2.45 g of sodium cyanoborohydride, 2.57 g of the title compound were obtained having an Rf=0.38 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[F:30]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=1[F:30])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)c(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium (0.452 g) in tetrahydrofuran (20 mL), 1-bromo-2,3,4-trifluorobenzene (2.21 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (25 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 4.2 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[O:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].CC(C)=[O:31]>O>[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[O:6][C:5](=[O:31])[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15]
Reactant: CC(C)=O
Reactant: CC1(c2ccc(Oc3ccccc3)cc2)OC(=S)N(Nc2ccccc2)C1=O
Solvent: O
Product: CC1(c2ccc(Oc3ccccc3)cc2)OC(=O)N(Nc2ccccc2)C1=O
Temperature: 50 °C

Procedure:
A solution of 5-methyl-5-(4-phenoxyphenyl)-3-phenylamino-2-thioxooxazolidin-4-one (2 g, 0.0051 moles) in 50 mls of acetone (0.1M) was treated at room temperature with a solution of KHSO5OXONE®, 4.72 g, 0.0154 moles) in 20 mls of water. The white slurry was heated at 50° C. for two hours then cooled to room temperature and filtered. The residue was washed with fresh acetone and the filtrates were evaporated under reduced pressure until all the acetone distilled away. The residue was dissolved in methylene chloride and washed with water and brine. The organic layer was dried (MgSO4), filtered, and evaporated to give the crude product. Recrystallization from 1-chlorobutane and petroleum ether afforded 1.68 g (88% of theoretical) of pure product as a white solid with a melting point of 140°-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([O-:11])=[O:10].[Na+].O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
3-Bromophenol (32.9 g, 0.19 mol) was added slowly to a cold (10° C.) solution of sodium nitrate (29.0 g, 0.34 mol) in conc. sulfuric acid; (40.0 g) and water (70.0 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Water (200 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to afford first the title compound (8.1 g, 20%), mp 40-42° C., then the undesired isomer, 3-bromo-4-nitrophenol, as a yellow solid (12.7 g, 31%). mp 125-127° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[Cl:28]C1C=C(C)C=CN=1>>[Cl:28][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][N:1]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: Cc1ccnc(Cl)c1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 2-chloro-4-methylpyridine provided the title compound. MS: (M+H m/z=389.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18]O)=[CH:5]2.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18][Cl:22])=[CH:5]2
Reactant: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)cc(F)c21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)CCn1c(CCl)cc2cc(Cl)cc(F)c21

Procedure:
A solution of {5-chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methanol (130 mg, 0.43 mmol) in 40 mL of DCM was stirred with SOCl2 (254 mg, 2.13 mmol) at RT and the reaction was monitored by LC/MS. After all starting materials were consumed, the mixture was concentrated in vacuo to afford the crude 5-chloro-2-(chloromethyl)-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indole, which was used for next step directly.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:7](=[CH2:8])[CH:6]([CH3:9])[CH2:5][C@@H:4]([OH:10])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:6]1[CH2:5][C@H:4]([OH:10])[CH2:3][C:2]([CH3:11])([CH3:1])[C:7]=1[CH3:8]
Reactant: C=C1C(C)C[C@@H](O)CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(C)(C)C[C@@H](O)C1
Yield: 92.5 %

Procedure:
4 g of (1R)-3,3,5-trimethyl-4-methylene-1-cyclohexanol obtained in Example 2A were dissolved in 50 ml of toluene, about 6 mg of p-toluenesulfonic acid were added and the mixture was refluxed for 45 min. It was then poured into 50 ml of water and extracted twice with 50 ml of ether. The organic phase was separated off, washed with 50 ml of saturated NaHCO3 solution, dried over MgSO4 and freed of solvent under reduced pressure. The residue was chromatographed on 150 g of silica gel with hexane/EA (4:1) to result in 3.7 g of the abovementioned product in the form of pale yellow crystals with a purity of 97% according to GC.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]2[C@@H:8]([C@H:9]2[C:11]([O:13]C(C)(C)C)=[O:12])[C@:7]([NH:25]C(OC(C)(C)C)=O)([C:18]([O:20]C(C)(C)C)=[O:19])[C@@H:6]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)(=[O:3])[CH3:2].C(O)(=O)C>O>[C:1]([NH:4][C@H:5]1[C@@H:10]2[C@@H:8]([C@H:9]2[C:11]([OH:13])=[O:12])[C@:7]([NH2:25])([C:18]([OH:20])=[O:19])[C@@H:6]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)O)[C@H]2[C@](N)(C(=O)O)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
Di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-(acetylamino)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.40 g, 3.81 mmol) is added to acetic acid (7.99 g, 7.62 mL, 133.05 mmol,) and water (3.81 mL, 3.81 g, 211.60 mmol) and heated in a microwave to 140° C. After 15 minutes, cool to room temperature, dilute with water and filter to collect the solids. Sequentially wash the solids with water (2×50 mL) and diethyl ether (2×50 mL), and then dry in a vacuum oven giving the title compound (1.23 g, 2.95 mmol, 77%): MS (m/z): 417/419 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To acid 102 (3.68 g, 0.014 mol) in THF (100 mL) at 0° C. was added BH3.Me2 (36 mL of a 2 M solution in THF, Aldrich) upon which the solution was warmed to room temperature. After 15 hours ice was carefully added (in order to control the effervescence) to the solution followed by brine. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. Flash chromatography (4:1 hexane/EtOAc) gave alcohol 103 as an oil (2.0 g, 59%). 13C NMR (100 MHz; CDCl3) 173.56, 80.85, 65.91, 39.74, 39.20, 38.90, 35.65, 29.99, 28.31, 20.18, 19.99, 14.56.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[CH3:23][C@H:24]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[O:35])[NH:25]1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:25]2[C@@H:24]([CH3:23])[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][C:26]2=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-Bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.