Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[C:15]([O:21][CH2:4][CH2:3][O:2][CH3:1])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COCCBr
Reactant: COc1ccc(O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(OC)c(Br)c1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
2-bromoethyl methyl ether (0.07 mL, 0.74 mmol) was added to a mixture of potassium carbonate (136 mg, 0.99 mmol) and 3-bromo-4-methoxy-phenol (100 mg, 0.49 mmol) in DMF (2 mL) and mix heated at 100° C. for 1 hr. Reaction mixture was allowed to cool and partitioned between ethyl acetate (20 mL×2) and water (20 mL). The combined organic phases were washed with sat. aqueous sodium chloride solution (40 mL) and dried over sodium sulphate. Solvents were removed in vacuo to afford a crude oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford the title compound (113 mg, 88%) as a colourless liquid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=S)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.[NH2:24][CH2:25][CH:26]([OH:32])[C:27]([O:30][CH3:31])([CH3:29])[CH3:28]>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[N:24][CH2:25][CH:26]([OH:32])[C:27]([O:30][CH3:31])([CH3:29])[CH3:28])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: COC(C)(C)C(O)CN
Agent: Cl[Hg]Cl
Solvent: CCO
Product: COC(C)(C)C(O)CN=C1NC[C@H](c2cccc(F)c2F)C[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (400 mg, 1.17 mmol) in ethanol (11.7 mL) was added 1-amino-3-methoxy-3-methylbutan-2-ol (389 mg, 2.92 mmol) and mercury (II) chloride (412 mg, 1.52 mmol). The mixture was stirred 20 min, filtered, and concentrated giving the crude title compound. MS 442.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16](C(OC(C)(C)C)=O)=[CH:15][CH2:14][N:13]2[C:26]([O:28]C(C)(C)C)=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14][N:13]2[C:26]([OH:28])=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2C=CC(C(=O)OC(C)(C)C)=CCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2C=CC=CCN2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The t-butyl 1-[(4-methoxyphenyl)sulfonyl]-5-(t-butoxycarbonyl)-diazepine-2-carboxylate (0.45 g, 0.95 mmol) is dissolved in methylene chloride (1.5 mL) and cooled to 0° C. in an ice bath. Trifluroacetic acid (1.5 mL, 19.0 mmol) was added and the resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture is warmed to room temperature and 1 mL of TFA is added. The reaction mixture is again stirred for an additional hour and the mixture is then concentrated down in vacuo. The residue is carried forward without further purification. The product is obtained as a TFA salt.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=[O:20])=[CH:13][CH:12]=1.ClCCl>N1CCC[C@@H]1C(O)=O>[Cl:1][CH:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[CH:19]=[O:20]
Reactant: COc1ccc(CCC=O)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@H]1CCCN1
Solvent: ClCCl
Product: COc1ccc(CC(Cl)C=O)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
N-Chlorosuccinimide (980 mg, 0.0073 mol) was added to a mixture of 3-(4-methoxyphenyl)propanal (1.0 g, 6.1 mmol) and D-proline (40 mg, 0.3 mmol) in dichloromethane (10 mL, 200 mmol) at 0° C. The reaction mixture was warmed to RT after 1 h, quenched with water, and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes to give the desired product (860 mg). 1H NMR (400 MHz, CDCl3): 9.52 (s, 1H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.36 (m, 1H), 3.80 (s, 3H), 3.32 (m, 1H), 3.02 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)(=[O:18])=[O:17])=[CH:12][C:11]=2[C:27]#[N:28])[CH:5]=[N:6][C:7]=1F.[NH:29]1[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:29]1([C:7]2[N:6]=[CH:5][C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)(=[O:18])=[O:17])=[CH:12][C:11]=3[C:27]#[N:28])=[CH:3][C:2]=2[Cl:1])[CH2:32][CH2:31][CH2:30]1
Reactant: C1CNC1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cnc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cnc(N2CCC2)c(Cl)c1
Temperature: 50 °C

Procedure:
To a solution of 4-((5-chloro-6-fluoropyridin-3-yl)oxy)-3-cyano-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Example 242, 200 mg, 0.47 mmol) in dimethylsulfoxide (2 mL) was added azetidine (54 mg, 0.94 mmol) followed by potassium carbonate (130 mg, 0.94 mmol) and the reaction was heated to 50° C. for 17 hours. The mixture was filtered and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3OC)cccc2c1N
Yield: 72.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,4-dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were reacted to afford the title compound (88 mg, 75.1% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H), 7.84 (dd, J=8.2 Hz, J′=1.4 Hz, 1H), 7.75 (dd, J=7.1 Hz, J′=1.4 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.29 (m, overlapped with CHCl3), 6.58-6.60 (m, 2H), 3.87 (s, 3H), 3.69 (s, 3H), 3.45 (q, 6.7 Hz, 2H), 1.65 (m, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.94 min.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:27]1([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[CH2:29][CH2:28]1>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:36][CH:33]4[CH2:34][CH2:35][N:30]([CH:27]5[CH2:29][CH2:28]5)[CH2:31][CH2:32]4)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCN(C2CC2)CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
N-benzyl-N-methyl-4-oxopiperidiumbromide (3.68 g) in water (6 ml) was added portionwise over 30 minutes to a stirred mixture of N-cyclopropylamine (0.404 g) and potassium carbonate in ethanol (15 ml) at 75° C. The mixture was stirred at 75° C. for 45 minutes. The reaction mixture was evaporated, took up into water (20 ml) and extracted into methylene chloride. The organic extracts were combined and concentrated under reduced pressure and the residue was triturated with ether and the soluble fraction was isolated by evaporation (1.11 g) to give N-cyclopropyl-4-piperidone; NMR Spectrum: (CDCl3) 0.50 (m, 4H), 1.73 (m, 1H), 2.40 (t, 4H), 2.91 (t, 4H). B) Sodium borohydride (0.085 g) was added to a stirred solution of N-cyclopropyl-4-piperidone (0.312 g) in ethanol under an atmosphere of argon. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, took up into water (20 ml) and extracted into methylene chloride. The organic extracts were combined and concentrated under reduced pressure to give N-cyclopropyl-4-piperidinol (0.298 g); NMR Spectrum: (CDCl3) 0.50 (m, 4H), 1.35 (s, 1H), 1.55 (m, 2H), 1.86 (m, 2H) 2.34 (m, 2H), 2.89 (m, 2H), 3.70 (m, 1H). C) Using an analogous procedure to that described paragraph (A) in the portion of Example 15 which is concerned with the preparation of starting material, N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide was reacted with N-cyclopropyl-4-piperidol to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy]-2-nitrobenzamide; Mass Spectrum: M+H+ 479.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][CH2:22][CH2:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:33]=[O:34])[CH:17]=2)[N:12]=[C:11]([N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][CH2:22][CH2:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a cooled solution of 4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was added anhydrous N,N-dimethylformamide (150 μL, 1.94 mmol) at −78° C. After being stirred at −78° C. for 30 minutes, the mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 410 mg of the crude product as a yellow solid. MS obsd. (ESI+) [(M+H)+] 428.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@:9]1([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:25]1([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([C:13]([N:32]1[CH2:33][CH2:34][CH2:35][N:29]([CH:25]2[CH2:26][CH2:27][CH2:28]2)[CH2:30][CH2:31]1)=[O:15])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CC(N2CCCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(Cc1cccc(F)c1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@]1(Cc1cccc(F)c1)C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
A mixture of (2S)-2-(3-fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (97.0 mg, 0.3 mmol), 1-cyclobutyl-[1,4]diazepane hydrochloride (75.0 mg, 0.3 mmol), HOBt (49.0 mg, 0.36 mmol), EDC (69.2 mg, 0.36 mmol) and N-methylmorpholine (98.0 mg, 0.96 mmol) in CH2Cl2 (10 mL) was stirred at rt for 18 h. The reaction mixture was diluted with CH2Cl2, washed successively with 1 N NaOH and water, dried, and concentrated. The residue (210 mg) was purified by FCC to provide the title compound (47.0 mg, 34%). MS (ESI): mass calcd. for C26H38FN3O3, 459.60; m/z found, 460.2 [M+H]+. 1H NMR (CDCl3): 7.25-7.18 (m, 1H), 6.99-6.83 (m, 3H), 3.61-3.48 (m, 2H), 3.37-3.10 (m, 4H), 2.92-2.52 (m, 3H), 2.49-2.25 (m, 2H), 2.23-1.80 (m, 9H), 1.76-1.55 (m, 5H), 1.51-1.48 (m, 9H).
Reaction SMILES: CC(C)=[O:3].C1OC1CCCCCCC.C1OC1CCCCCCCC.[CH2:26]1[O:37][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].S(=O)(=O)(O)O>>[CH2:26]([OH:37])[CH:27]([OH:3])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCC1CO1
Reactant: CC(C)=O
Agent: CCCCCCCC1CO1
Agent: CCCCCCCCC1CO1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to a (1:1:1) mixture of 1-nonene oxide, 1-decene oxide, and 1-undecene oxide at room temperature. After adding 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and a mixture of 1,2-nonanediol, 1,2-decanediol and 1,2 undecanediol is obtained by distilling under vacuo.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O.N>C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:20][CH:19]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(/C=C/CO)cc1
Temperature: 155 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A mixture of 4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one (1.10 g, 5.0 mmol), (2E)-3-(4-bromophenyl)-2-propen-1-ol (1.28 g, 6 mmol), cuprous iodide (476 mg, 3 mmol), potassium carbonate (829 mg, 6 mmol) and DMF (20 mL) was stirred overnight at 155° C. The reaction liquid was cooled to room temperature, then poured into ammonia water, and ethyl acetate was added for extraction. The organic layer was washed with water and saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, followed by purification by flash column chromatography (KP-Sil, hexane:ethyl acetate=1:1 to 0:1) to obtain the entitled compound (881 mg).
Reaction SMILES: [H-].[Na+].I[CH3:4].[CH2:5]([C:12]1[CH:13]=[C:14]([N:18]2[CH2:22][C@H:21]([OH:23])[C@H:20]([OH:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([C:12]1[CH:13]=[C:14]([N:18]2[CH2:22][C@H:21]([O:23][CH3:4])[C@H:20]([OH:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@@H]1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@H]1O

Procedure:
This was synthesized in the same manner as in Production Example 11 except that 1 equivalent of each of sodium hydride and iodomethane were used to (3R,4S)-1-(3-Benzylphenyl)-3,4-dihydroxypyrrolidine (Production Example 10).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7](Br)[C@@H:6]1[N:21]=[N+:22]=[N-:23])(=[O:3])[CH3:2].[CH3:24][Si:25]([CH3:30])([CH3:29])[CH2:26][CH2:27][OH:28]>C(Cl)Cl.[Si]([O-])([O-])([O-])[O-].[Ag+].[Ag+].[Ag+].[Ag+]>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:28][CH2:27][CH2:26][Si:25]([CH3:30])([CH3:29])[CH3:24])[C@@H:6]1[N:21]=[N+:22]=[N-:23])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CCO
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ag+]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-D-galactopyranosyl bromide (6 g, 15.2 mmol), 2-(trimethylsilyl)-ethanol (2.7 g, 22.8 mmol) and powdered molecular sieves 4 Å (14.6 g) in dry CH2Cl2 (100 ml) was stirred under N2 for 1 h. Silver silicate (369) was added. After 20 min. stirring, the reaction mixture was filtered through celite and the filtrate was evaporated to dryness. Column chromatography (heptane-EtOAc 3:1) of the residue gave 23 (5.11 g, 78%) as a syrup. [α]D25 -18° (c 1, CHCl3).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH2:5][C:4](=[O:12])[NH:3]1.[OH-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[CH2:15]([O:22][C:23]([NH:8][CH:7]([CH:6]1[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[C:9]([OH:11])=[O:10])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O)C1CC(=O)NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1

Procedure:
In 250 ml of water-dioxane (1:1) was suspended 10 g of 2-(2,5-dioxopyrrolidin-3-yl)glycine and under cooling at 0°-5° C. the above amino acid was dissolved by addition of 70 ml of 1 N sodium hydroxide. To this solution was added 15 ml of benzyloxycarbonyl chloride and, with adjusting pH to 7.1-7.4 with sodium hydrogen carbonate, the mixture was stirred at the same temperature as above for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent and the concentrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid and allowed to stand in a refrigerator overnight to give crystals. Yield 15.8 g.
Reaction SMILES: O.O.[Na].[Na].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1)(O)=[O:6].[NH3:25]>S(Cl)(Cl)=O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1)(=[O:6])[NH2:25]
Reactant: N
Reactant: O=C(O)c1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: O
Product: NC(=O)c1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1

Procedure:
A suspension of 6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate (0.5 g) (see Example 13B) in thionyl chloride (10 cm3) was heated under reflux for 10 minutes. The cooled solution was evaporated in vacuo to afford a yellow solid which was treated without purification with aqueous ammonia solution (5 cm3, S.G. 0.88) with stirring. The solid material was filtered off and warmed with chloroform:methanol, 4:1, to remove soluble impurities and the remaining solid was filtered to afford the title compound, m.p. >320°, (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[Se:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:20](=[O:28])[CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[Se:9][C:10]([CH2:13][O:14][C:18]3[C:23]([CH3:24])([CH3:25])[O:22][C:21]([CH3:27])([CH3:26])[C:20](=[O:28])[CH:19]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(C)(C)C(Cl)=CC1=O
Reactant: OCc1cnc(-c2ccc(Cl)cc2)[se]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(C)(C)C(OCc2cnc(-c3ccc(Cl)cc3)[se]2)=CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a solution of [2-(4-chlorophenyl)selenazol-5-yl]methanol (300 mg, 1.1 mmol) in dry tetrahydrofuran (5 ml) under an atmosphere of nitrogen is added, in one portion, the sodium hydride (44 mg, 1.1 mmol). The reaction mixture is stirred for 5 minutes at room temperature and 5-chloro-2,2,6,6-tetramethyl-6H-pyran-3-one (208 mg, 1.1 mmol) is added in one portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, and the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel to give 5-[2-(4-chlorophenyl)selenazol-5-ylmethoxy]-2,2,6,6-tetramethyl-6H-pyran-3-one (261 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:18][C:19]2[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]3[N:28]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:29]=[CH:30][C:20]=23)([CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Ni]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:18][C:19]2[C:24]([NH2:25])=[CH:23][N:22]=[C:21]3[N:28]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:29]=[CH:30][C:20]=23)([CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC1(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 3-(1-Benzene sulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-methyl-piperidine-1-carboxylic acid benzyl ester (400 mg, 0.73 mmol) and Raney Ni (1.0 g) in ethyl acetate (20 mL) was hydrogenated at 25° C. for 1.5 hours. The mixture was filtered through Celite, thoroughly washing the filter cake with methanol. The filtrate and washings were combined and concentrated under vacuum to give about 380 mg (100%) of 3-(5-Amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-methyl-piperidine-1-carboxyli c acid benzyl ester without further purification. LCMS (Method J, ESI): RT=1.04 min, m+H=519.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)=[O:15])[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2CCC(c3ccc(Cl)cc3)(c3ccc(Cl)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 25D (0.8 g, 2.2 mmol) in CH2Cl2 (30 mL) was added tert-butyl piperazine-1-carboxylate (0.41 g, 2.2 mmol) under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.84 g, 4.4 mmol) and 4-(dimethylamino)pyridine (0.027 g, 0.22 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; (CH3OH/CH2Cl2, 2:98 eluant) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19]C(Cl)Cl.ClCCl>>[C:1]([C:5]1[CH:14]=[C:13]([CH:18]=[O:19])[C:12]2[CH2:11][CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]=1[OH:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1ccc2c(c1O)C(C)(C)CCC2
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c2c(c1O)C(C)(C)CCC2
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution of 2-tert-butyl-8,8-dimethyl-5,6,7,8-tetrahydronaphthol (9.5 g, 40.5 mmole) and 1,1-dichloromethyl methyl ether (5.17 g, 45 mmole) in dry dichloromethane (200 ml) stannic chloride (15.63 g, 60 mmole) was added dropwise at -58°. The mixture was warmed to 0° over 45 minutes, poured into ice water (300 ml) and extracted with diethyl ether (3×150 ml). The ether extracts were washed with water and aqueous saturated sodium chloride, dried and evaporated to give 3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-1-naphthaldehyde as a crystalline solid (9.49 g, 90%), m.p. 143°-45°.