Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[NH:17][CH:16]=[CH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[N:5]1.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].ClCCl>CN(C)C=O>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH3:3])[CH:8]=3)[CH:10]=2)[CH:15]=[CH:16]1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: Cn1cc(-c2cnc3cc[nH]c3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ncc(-c3cnn(C)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
In a N2 charged round bottom flask, Sodium Hydride, 60%, (41 mg, 1.01 mmol) was suspended in dimethylformamide (2.5 mL). The solution was maintained under N2 and cooled to 0° C. for 10 minutes. Next, 6-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) was dissolved in dimethylformamide (2.5 mL) and added to the cooled solution dropwise. The solution was allowed to stir at 0° C. for an additional 10 minutes. Finally, Bromo-acetic acid ethyl ester (123 uL, 1.11 mmol) was slowly added to the reaction vessel. The reaction was allowed to equilibrate back to room temperature, while stirring for 2 hours. Finally, the solution was transferred to a separatory funnel with dichloromethane (75 mL) and washed with water (2×75 mL). The organic layer was dried over Na2SO4, concentrated down and purified by flash chromatography (0-10% Methanol/dichloromethane step gradient) to afford the title compound (122 mg, 43% yield). MS m/z=285 [M+H+]+
Reaction SMILES: ClC1C=C(C=CC=1)C([O-])=O.[Br:11][C:12]1[CH:13]=[C:14]2[CH:21]=[CH:20][NH:19][C:15]2=[N+:16]([OH:18])[CH:17]=1.C(=O)(O)[O-].[Na+]>O>[Br:11][C:12]1[CH:13]=[C:14]2[CH:21]=[CH:20][NH:19][C:15]2=[N+:16]([O-:18])[CH:17]=1
Reactant: O[n+]1cc(Br)cc2cc[nH]c21
Agent: O=C([O-])O
Agent: O=C([O-])c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Product: [O-][n+]1cc(Br)cc2cc[nH]c21
Yield: 71 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (20 g, 0.1 mol) was suspended in 300 mL of NMP. A solution of 3-Chloroperbenzoic acid (40 g, 0.16 mol) in 100 mL NMP was added dropwise over 30 min. The solution was stirred at 23° C. for 1 h after which 600 mL of ether were added. The grey precipitate was filtered off and washed with ether to yield 18 g of 5-Bromo-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate. The filtrate was stirred with 250 mL saturated sodium bicarbonate solution and 250 mL water to give 5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (4.3 g, 20.2 mmol). The filtered 5-Bromo-7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate was suspended in 200 mL of water and 200 mL of saturated sodium bicarbonate solution and was vigorously stirred for 1 h. The grey solids were filtered and washed with water to give a second crop of 5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (11.15 g, 52.3 mmol, 71% combined yield). 1H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 7.9 (d, J=1.5 Hz, 1H), 7.5 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H). MS: m/z 212.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([OH:21])=O.O[N:23]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([NH2:23])=[O:21]
Reactant: On1nnc2ccccc21
Reactant: Nc1sc(-c2ccc(N3CCOCC3)nc2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N
Temperature: 25 °C
Reaction time: 36 h

Procedure:
5-Amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylic acid (310 mg, 1.01 mmol), 1-hydroxybenzotriazole (310 mg, 2.02 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), and ammonium chloride (271 mg, 5.06 mmol) were taken up in dimethylformamide (20 mL) under argon. Diisopropylethylamine (0.88 mL, 5.06 mmol) was added and the mixture was stirred at ambient temperature for 36 hours. The mixture was then concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-10% methanol/ethyl acetate) to afford the title compound. LRMS (APCI) calc'd for (C13H16N5O2S) [M+H]+, 306.1; found 306.0.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>CN(C)C=O>[Br:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)OCCO2
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCCO2
Reaction time: 24 h

Procedure:
35 g of 1,4-benzodioxane and 200 ml of anhydrous dimethylformamide are placed under argon at 0° C. 54.9 g of N-bromosuccinimide are then added in portions. After it has returned gradually to room temperature, the reaction mixture is stirred for 24 hours. The solvents are evaporated off under reduced pressure and the white solid obtained is washed with dichloromethane. The filtrate is treated with 50 ml of saturated aqueous sodium sulfate solution, washed with 50 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, a yellow oil is obtained (quantitative yield).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:28][F:29])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:27])(=[N:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:14][CH:13]=1)[OH:11].C([O:32][C:33](=O)[CH:34]([Cl:36])[Cl:35])C>CO>[Cl:35][CH:34]([Cl:36])[C:33]([NH:8][C@H:9]([CH2:28][F:29])[C@H:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:27])(=[N:20][C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])=[O:19])=[CH:16][CH:17]=1)=[O:32]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a solution of (1R,2S)-2-Amino-3-fluoro-1-(4-(methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)phenyl)-propan-1-ol TFA salt (426 mg, 1.479 mmol) in Methanol (5 mL) is added TEA (0.299 mL, 2.95 mmol) followed by addition of ethyldichloroacetate (0.279 mL, 1.775 mmol) The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo to get crude which is purified by combi-flash chromatography using 10.3% MeOH in DCM as an eluent to afford title compound (212 mg) as yellow oil. 1H-NMR (400 MHz, DMSO) δ: 3.02 (s, 3H), 4.19-4.13 (m, 1H), 4.15 (bs, 1H), 4.36-4.41 (m, 1.5H), 4.44-4.56 (m, 1H), 4.66-4.69 (m, 0.5H), 4.93 (t, J=4.56 Hz, 1H), 6.0 (d, J=4.64 Hz, 1H), 7.54 (d, J=8.28 Hz, 2H), 7.87 (d, J=8.36 Hz, 2H), 9.49 (d, J=8.36 Hz, 1H). LC-MS (m/z): M+H=343.1 (fragment).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:9][CH2:8][C@@:7]([NH:18][C:19]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:20])([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C@H:6]([C@@H:30](O)[CH2:31][O:32][CH3:33])[CH2:5]2)[CH2:3][CH2:2]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([C@@H:4]2[O:9][CH2:8][C@:7]3([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])[N:18]=[C:19]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C@H:30]([CH2:31][O:32][CH3:33])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COC[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Product: COC[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
rel-N-({(3S,4R,6R)-6-Cyclopropyl-3-(2,4-difluorophenyl)-4-[(1R)-1-hydroxy-2-methoxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C41) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1, except that the reaction was warmed to room temperature and allowed to proceed for 18 hours before work-up. The product was obtained as a solid. Yield: 17 mg, 36 μmol, 51%. LCMS m/z 473.3 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.24 (br d, J=7 Hz, 2H), 7.49-7.54 (m, 1H), 7.36-7.48 (m, 3H), 6.83-6.95 (m, 2H), 4.09 (br d, J=12 Hz, 1H), 3.82 (d, J=12.1 Hz, 1H), 3.62-3.69 (m, 1H), 3.37-3.45 (m, 2H), 3.34 (s, 3H), 3.09-3.16 (m, 1H), 2.94 (ddd, J=10.9, 8.2, 2.3 Hz, 1H), 1.80-1.92 (m, 1H), 1.68-1.76 (m, 1H), 0.50-0.61 (m, 2H), 0.40-0.47 (m, 1H), 0.24-0.31 (m, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.[CH3:14]CN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3][N:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cncc2ccccc12
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a stirred solution of isoquinolin-4-carboxylic acid (Intermediate-14) (1.2 g, 6.9 mmol) in CH2Cl2 (10 mL) was added, EDCI (1.3 g, 8.3 mmol), HOBt (1.12 g, 8.3 mmol), DMAP (84 mg, 0.7 mmol) and the mixture was stirred at RT for 20 min. To this, MeOH (0.33 g, 10.4 mmol) was added and the reaction mixture was further stirred at RT for overnight. It was diluted with CH2Cl2 (100 mL) and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude product that was purified by flash column chromatography (10% EtOAc:Hexanes) to give the desired product (700 mg, 54%) as pale yellow solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH2:27][CH2:26]2)=[C:21]([Cl:36])[CH:20]=1>C(Cl)Cl>[Cl:36][C:21]1[CH:20]=[C:19]([NH:18][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH2:27][CH2:26]1
Reactant: CC(C)C(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
According to Scheme 4 Step 3: Picolinoyl chloride hydrochloride (0.93 mmol, 178 mg) and Et3N (1.86 mmol, 0.26 mL) were added to a solution of 1-(4-(4-amino-2-chlorophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62 mmol, 175 mg) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over C18 column using water/ACN (60:40) as eluent to afford N-(3-chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamide (0.11 mmol, 42 mg, 18%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:13]([C:14]([C:25](=[O:38])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3C3C=CC=CC=3)=[C:15]([CH2:23][CH3:24])[C:16]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCCCCC>[C:25]([C:14]1[N:13]2[C:17]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=[CH:12]2)=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]=1[CH2:23][CH3:24])(=[O:38])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1c(CC)c(C(=O)c2ccccc2-c2ccccc2)n2cccc(OCc3ccccc3)c12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1c(CC)c(C(=O)c2ccccc2)n2cccc(OCc3ccccc3)c12
Yield: 79 %

Procedure:
Mp, 124-125° C. (AcOEt-hexane). 79% Yield. Ethyl (8-benzyloxy-2-ethyl-3-(o-phenylbenzoyl)indolizin-1-yl)carboxylate 26b. Mp, 110-112° C. (ether-hexane). 46.0% Yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[N:11]=[C:5]2[CH:4]=1)#[N:2].[C:21]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])([CH3:24])([CH3:23])[CH3:22].CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH:29][CH2:28][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:30])=[O:18])=[CH:19][CH:20]=3)[N:11]=[C:5]2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccn2cc(-c3ccc(C(=O)O)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cn3ccc(C#N)cc3n2)cc1

Procedure:
6.6 g of 4-(7-cyanoimidazo[1,2-a]pyridin-2-yl)benzoic acid [obtainable as in Example 5]in 100 ml of dichloromethane and 25 ml of DMF are stirred with 4.5 g of β-alanine tert-butyl ester in the presence of 5.25 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and 6 ml of N-methylmorpholine at room temperature for 20 h. This is followed by extraction 3-4 times with 30 ml of water each time, evaporation and the customary working-up. Tert-butyl 3-[4-(7-cyanoimidazo[1,2-a]pyridin-2-yl)benzamido]propionate is obtained, m.p. 212° (decomposition).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1ccc(CCl)cc1
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
To 4-chloromethylbenzoyl chloride (1.03 g, 5.47 mmol) in DCM (20 mL) at 0° C., add with stirring triethylamine (0.839 mL, 6.02 mmol) followed by cyclohexylamine (0.688 mL, 6.02 mmol), and continue stirring for 15 min. Dilute the reaction mixture with aqueous 1M hydrochloric acid, extract three times with EtOAc, wash with water and saturated aqueous NaHCO3. Dry the combined organic extracts over anhydrous Na2SO4 and concentrate in vacuo to give the title compound as a white solid (1.31 g, 95%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][NH:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:20][N:21]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: CNC1CCCC1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Product: CN(c1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12)C1CCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with N-methylcyclopentylamine to obtain 4-(N-methylcyclopentylamino)-7-nitro-5-cyano-2-trifluoromethylbenzimidazole, m.w., 353.3.
Reaction SMILES: C(O)[C@@H](O)[C@H:3]([OH:13])[C@@H:4]([OH:12])[C@@H:5]([OH:11])[C@@H:6]([OH:10])[C:7]([O-])=[O:8].O.O.[Na+]>O.O.O.O.O.O.[Co](Cl)Cl.O>[O:8]=[CH:7][C@H:6]([C@@H:5]([C@@H:4]([CH2:3][OH:13])[OH:12])[OH:11])[OH:10]
Reactant: O=C([O-])[C@H](O)[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl[Co]Cl
Agent: [Na+]
Solvent: O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Sodium glucoheptonate dihydrate (71.3 g/0.25 mole), cobalt chloride hexahydrate (0.12 g/0.50 mmole) and water (500 ml) are introduced into a double envelope reactor. The mixture is brought to a temperature of 30° C. and to a pH of 6.5 by the addition of soda 2N. The water, oxygenated to 30% (77 ml/0.75 mole), is introduced over 75 minutes, maintaining the temperature between 30 and 35° C. and the pH at 6.5 with the aid of soda 2N. When the addition is finished, the solution is agitated for a further hour. The pH is brought to 2.5 by the addition of concentrated sulphuric acid (8 ml). The pink solution has the following composition:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[C:18]([C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([CH2:7][N:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]3)[S:5][CH:6]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(C)=O)c3)cs2)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a solution (4 mL) of the compound (250 mg, 0.79 mmol) obtained in Example 30c in 1,2-dimethoxyethane were added (3-acetylphenyl)boronic acid (156 mg, 0.95 mmol), potassium carbonate (218 mg, 1.58 mmol) and tetrakistriphenylphosphinepalladium (91 mg, 0.079 mmol), and the mixture was stirred at 120° C. for 15 min under microwave conditions. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=1/1) to give the title compound (188 mg, 67%) as a pale-brown oil.
Reaction SMILES: [CH3:1][SiH:2]([CH3:26])[O:3][CH:4]([C:20]([CH3:25])([CH3:24])[CH:21]([CH3:23])[CH3:22])[C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([OH:18])=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:19])[NH:7][CH2:6]1.[CH:27]([N:30]1[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]1)([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH3:1][SiH:2]([CH3:26])[O:3][CH:4]([C:20]([CH3:24])([CH3:25])[CH:21]([CH3:22])[CH3:23])[C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([O:18][CH:33]4[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]4)=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:19])[NH:7][CH2:6]1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C(O[SiH](C)C)C(C)(C)C(C)C)CNC2=O)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 1, from (S)-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow foam (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=C[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])=[CH:9][C:8]=1O)=[O:5].ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:64](CC)CC)C>C(#N)C.O>[Cl:1][C:2]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)[CH:27]=[CH:26][C:3]=1[C:4]1[O:5][C:8]2[CH:9]=[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH3:14])[N:64]=[CH:24][C:7]=2[N:6]=1
Reactant: C[C@@H](COc1ccc(NC(=O)c2ccc(OCC3CC3)cc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)cc3Cl)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl ((2S)-1-(4-((2-chloro-4-(cyclopropylmethoxy)benzoyl)amino)-3-hydroxyphenoxy)propan-2-yl)carbamate (200 mg), hexachloroethane (241 mg) and triphenylphosphine (321 mg) in acetonitrile (3 mL) was added triethylamine (0.454 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: ClCc1ccc(Cl)cc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-chlorobenzylchloride to form 1-(4-chlorobenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 237°-239° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3([CH3:27])[CH2:26][CH2:25]3)[C:5]2=[CH:4][CH:3]=1.[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32].Br[CH2:38][C:39]([NH2:41])=[O:40].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:41][C:39]([CH2:38][N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:28])[CH:11]1[C:24]1([CH3:27])[CH2:25][CH2:26]1)=[O:40].[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32]
Reactant: NC(=O)CBr
Reactant: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C2N(CC(N)=O)C(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (800 mg, 1.36 mmol) and 2-bromo-acetamide (938 mg, 6.8 mmol) in DMF (1 mL) was added Cs2CO3 (4.4 g, 13.4 mmol). The mixture was stirred at 50° C. for 1.5 h, then purified by column chromatography to give title compound (60 mg, 6.8%).