Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][N:14]=[C:13]([NH2:20])[N:12]=2)=[CH:4][CH:3]=1.CN(C=O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[C:16]([NH2:17])=[CH:15][N:14]=[C:13]([NH2:20])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(-n2ncc3ccc(I)cc32)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncc(N)c(-n2ncc3ccc(I)cc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a suspension of 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine (200 mg, 45% purity, 0.236 mmol) in a mixture of methanol (4 mL), DMF (3 mL) and water (3 mL) was added sodium dithionite (205 mg, 1.178 mmol) and sodium bicarbonate (99 mg, 1.178 mmol). The suspension was stirred at RT for 2 hr. After 2 hr LC-MS (Method B) showed 11% of desired product, 15% of starting 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine (16-a) and 67% of degraded by-product. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2×10 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound; m/z=+352.9 (M+H)+, (purity=11%). This intermediate was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Mg].CN([CH:14]=[O:15])C>C1COCC1.C(Cl)Cl>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Br:8])[CH:5]=1)[CH:14]=[O:15]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cc(Br)c1
Reaction time: 5 h

Procedure:
A mixture of 15.7 g (50 mmoles) of 1,3,5-tribromobenzene and 1.344 g (56 mmoles) of magnesium in 200 mL of THF was stirred 5 hrs. At room temperature 7.5 mL (100 mmoles) of DMF was then added at 0° and the reaction mixture was stirred overnight. Solvent was removed in vacuo at room temperature the residue was taken up in 200 mL of ethyl acetate and washed with 6×50 mL of satd. sodium chloride soln. The organic phase was dried over anhyd. MgSO4. Solvent was removed to give a crude solid, which was dissolved in minimum amount of methylene chloride, and applied on silica gel. Elution with 1:9 mixture of ether:hexane mixture containing 3% methylene chloride gave the desired 3,5-dibromobenzaldehyde as white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH3:25])[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:23])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][CH:11]=1)[CH3:2]>O=[Mn]=O>[CH2:24]([CH:3]([CH2:1][CH3:2])[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12](=[O:23])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=[CH:10][CH:11]=1)[CH3:25]
Reactant: CCC(CC)CNc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1
Agent: O=[Mn]=O
Product: CCC(CC)CNc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1

Procedure:
Oxidation of tert-butyl 3-(3-(2-ethylbutylamino)phenyl)-3-hydroxypropylcarbamate by MnO2 following the method used in Example 12 gave tert-butyl 3-(3-(2-ethylbutylamino)phenyl)-3-oxopropylcarbamate as a pale yellow oil. Yield (0.350 g, 86%); 1H NMR (400 MHz, DMSO-d6+5% D2O) δ 7.17 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.04 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 3.20 (t, J=6.4 Hz, 2H), 3.03 (t, J=6.8 Hz, 2H), 2.90 (d, J=6.0 Hz, 2H), 1.50-1.44 (m, 1H), 1.31 (s, 9H), 1.28-1.19 (m, 4H), 0.82 (t, J=7.6 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:22]=[C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:10]1[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:3][CH2:4]1
Reactant: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 14, 70 mg, 0.24 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (42 mg, 0.24 mmol) and sodium triacetoxy borohydride (150 mg, 0.75 mmol) were reacted as described for Example 5. Chromatography on silica gel with dichloromethane/methanol (6:1) and crystallization from ethyl acetate/hexanes gave the product as a colorless solid, 73 mg (67%), mp 212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31](OC)=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:32][CH2:31][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:35][CH2:36][O:37][CH3:38])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=2)[CH:11]1[C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CO)C2c1ccc2c(c1)OCO2
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of methyl (1RS,2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (4.45 g, 8.5 mmol) in THF (35 ml) stirred at 0° C. was added lithium aluminum hydride (17 ml of a 1M solution in THF). The cooling bath was removed and stirring continued for 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as an oil (4.13 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NN2CCOCC2)cn1
Yield: 60 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (62 mg, 60%) which was obtained as a white solid. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:13])[N:6]=[CH:5]2.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1)[CH3:13])[N:6]=[CH:5]2
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1ncc2cc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2ncc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 4-[N-(6-chloro-2-quinazolinyl)-N-methylamino]phenol (0.52 g), ethyl 2-bromopropionate (0.40 g), potassium carbonate (0.28 g) and methyl ethyl ketone (25 ml) was heated under reflux for a period of 18 hours. After cooling, the mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The dichloromethane extract was dried (anhydrous sodium sulfate) and the solvent was removed under reduced pressure. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(6-chloro-2-quinazolinyl)-N-methylamino]phenoxy}propionate as a yellow oil. The assigned structure was confirmed by proton magnetic resonance (pmr) spectroscopy and mass spectrometry. Pmr spectrum (CDCl3 ; δ in ppm): 8.93 (1H, s, quinazoline hetero ring proton); 7.60 (3H, s, quinazoline benzo-ring protons); 7.13 (4H, d of d, phenoxy protons); 4.80 (1H, q, CH--CH3); 4.27 (2H, q, CH2 --CH3); 1.60 (3H, d, CH--CH3); 1.27 (3H, t, CH2 --cH3).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:8][OH:9])[CH2:7][O:6][CH2:5]1.[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22](OCC(Cl)(Cl)Cl)=[O:23])([CH3:12])[CH3:11]>C1COCC1>[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22]([O:9][CH2:8][C:4]1([CH3:3])[CH2:7][O:6][CH2:5]1)=[O:23])([CH3:12])[CH3:11]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: CC1(CO)COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC1(C)COC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.8 %

Procedure:
NaH (0.19 g, 4.80 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (10 mL), cooled to 0° C. and 3-methyl-3-oxetane methanol (0.41 g, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (1.33 g, 4.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 3-methyl-3-oxetane methanol in THF were added after 8 and 32 h, respectively. After 50 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5%, 10% and 20% MeOH in DCM (200 mL each)) and by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (3-methyloxetan-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (68.2 mg, 5.8%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.C[O-].[Na+].Cl>C1COCC1.ClCCl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.1 %

Procedure:
To a stirring solution of 2-aminopyridine 9 (2.00 g, 21.3 mmol) in THF (45 mL) were successively added dichloromethane (88 mL), 4-nitrobenzenesulfonyl chloride (9.89 g, 44.6 mmol), and triethylamine (6.51 mL, 46.75 mmol). The solution was heated to reflux for 2 h and the resultant light yellow solid was collected by filtration. This material was suspended in 200 mL of methanol and a large excess (>10 eq) of sodium methoxide was added. The mixture was stirred at r.t. for 6 h, treated with HCl 1N (2 mL) and concentrated in vacuo at 80° C. to 50 mL volume. This solution was transferred into an Erlenmeyer flask and further neutralized with 1N HCl. A precipitate was formed which was collected by filtration, washed with water and dried, to afford the title compound 10 (2.8 g, 47% yield). 1H NMR (DMSO-d6) δ (ppm): 8.32 (d, J=6.8 Hz, 2H), 8.07 (d, J=7.0 Hz, 2H), 7.92 (bs, 1H), 7.80 (bs, 1H), 7.26 (bs, 1H), 6.85 (bs, 1H). LRMS (ESI): (calc) 279.03 (found) 280.0 (MH+).
Reaction SMILES: O.O.O.O.C([O-])(=O)C.[Co+2:9].C([O-])(=O)C.C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:65]3[NH:66][C:62](=[CH:63][CH:64]=3)[C:61]([C:67]3[CH:72]=[CH:71][C:70]([C:73]#[CH:74])=[CH:69][CH:68]=3)=[C:60]3[N:75]=[C:57]([CH:58]=[CH:59]3)[C:56]([C:76]3[CH:81]=[CH:80][C:79]([C:82]#[CH:83])=[CH:78][CH:77]=3)=[C:55]3[NH:84][C:52]([CH:53]=[CH:54]3)=[C:51]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[CH:92])=[CH:87][CH:86]=3)[C:50]3=[N:93][C:47]=2[CH:48]=[CH:49]3)=[CH:42][CH:41]=1)#[CH:39].O>CN(C=O)C>[C:82]([C:79]1[CH:78]=[CH:77][C:76]([C:56]2[C:55]3[NH:84][C:52](=[CH:53][CH:54]=3)[C:51]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[CH:92])=[CH:87][CH:86]=3)=[C:50]3[N:93]=[C:47]([CH:48]=[CH:49]3)[C:46]([C:43]3[CH:44]=[CH:45][C:40]([C:38]#[CH:39])=[CH:41][CH:42]=3)=[C:65]3[NH:66][C:62]([CH:63]=[CH:64]3)=[C:61]([C:67]3[CH:68]=[CH:69][C:70]([C:73]#[CH:74])=[CH:71][CH:72]=3)[C:60]3=[N:75][C:57]=2[CH:58]=[CH:59]3)=[CH:81][CH:80]=1)#[CH:83].[Co:9]
Reactant: [Co+2]
Agent: C#Cc1ccc(-c2c3nc(c(-c4ccc(C#C)cc4)c4ccc([nH]4)c(-c4ccc(C#C)cc4)c4nc(c(-c5ccc(C#C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: [Co]

Procedure:
A solution of 8.71 g (35 mmol) of cobalt acetate tetrahydrate (Co(CH3COO)2.4H2O) in 100 ml of DMF was added portionwise to a solution of 1.7 g (2.39 mmol) of porphyrin TEPP (2) as obtained above in step 2), in 500 ml of DMF. The mixture obtained was refluxed for 20 hours. The heating was stopped and 150 ml of water were added to the reaction medium. The mixture was subsequently extracted with ethanol (4×200 ml) and the organic phase was then evaporated. The residue was dissolved in 300 ml of ethanol, and the organic phase was washed with 3×200 ml of water and dried over sodium sulfate. The solvent was evaporated off and the cobalt tetrakis(4-ethynylphenyl)porphyrin (Co-TEPP) (4) (1.19 g; 1.55 mmol; yield: 65%) was obtained in the form of a powder that was purple/black in color, and red in solution in chloroform.
Reaction SMILES: [C:1]1([C:7]2[S:29][C:10]3[N:11]([CH2:20][C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[CH:12]=[C:13]([NH:16]C(=O)C)[C:14](=[O:15])[C:9]=3[C:8]=2[CH3:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[S:29][C:10]3[N:11]([CH2:20][C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[CH:12]=[C:13]([NH2:16])[C:14](=[O:15])[C:9]=3[C:8]=2[CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccccc2)sc2c1c(=O)c(N)cn2Cc1c(F)cccc1F

Procedure:
The compound obtained in Example 4 was dissolved in ethanol, and to the solution was added an excess amount of an aqueous 2N sodium hydroxide solution. The mixture was subjected to alkali hydrolysis under heating for24 hours to give the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11]S[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[O:29][S:30]([O-:32])=O.[K+].CC([O-])=O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:30](=[O:32])(=[O:29])[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (2.05 g, 4.9 mmol) in THF-water 1:1 (60 mL) was added oxone (6.52 g, 10.3 mmol). After stirring the reaction mixture for 2 h at 40° C., 2 g NaOAc and 2 g sodium metabisulfite were added. The reaction mixture was stirred for 0.5 h, basified with saturated aq. K2CO3 solution and the product was extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from THF-hexane as yellow crystals: TLC (hexane-THF 1:1) Rf=0.23; HPLC RtA=1.76 min; ESIMS [M+NH4]+=454; 1H NMR (600 MHz, DMSO-d6): δ 7.32 (d, 2H), 6.91 (d, 1H), 3.73 (m, 1H), 3.0-3.2 (m, 5H), 2.94 (m, 1H), 2.74 (dd, 1H), 2.18 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:30][CH2:31][N:32]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:34]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCNCC6)c5)cc4c3C2)nc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCN(C(C)=O)CC6)c5)cc4c3C2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
To a stirred solution of methyl-2-{8-[3-(piperazin-1-ylmethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (1.5 g, 3.11 mmol) in dry DCM (50 mL) was added 4-dimethylaminopyridine (1.9 g, 15.57 mmol) and then acetic anhydride (0.35 mL, 3.72 mmol) was added at 0° C. and stirred for 5 min. The reaction mass was maintained at room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC, and after completion the reaction mass was diluted with water and extracted with DCM. The DCM layer dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give methyl-2-{8-[3-((4-acetylpiperazin-1-yl)methyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (1.4 g, 85.88%) with HPLC purity 99.25%; m/e=525 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].[CH2:14](Cl)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([C:3]1[CH:4]=[C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:6]2[N:7]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:8]=1)#[N:2]
Reactant: Cc1[nH]c2ncc(C#N)cc2c1C
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(C#N)cc-2c1C
Yield: 23.5 %

Procedure:
A mixture of 5-cyano-2,3-dimethyl-pyrrolo [2,3-b]pyridine (77 mg, 0.5 mmol ) and phenacyl chloride (650 mg, 4.2 mmol ) in 12 ml CH3CN was refluxed for 62 h. The mixture was basified with a saturated Na2CO3 solution and extracted with CH2Cl2. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed (silica, CH2Cl2 /diethyl ether;7/3) yielding 34 mg (26%) pure title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCCCCC>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a mixture of 0.72 g of 3-bromopropanol, 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of hexane, 0.06 g of tetra-n-butylammonium bromide and 5.0 g of water was added 0.77 g of a 27% aqueous sodium hydroxide solution. The mixture was heated to 60° C. and stirred for 4 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.2 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 92%, yield: 89%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].Br[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[O:15])[CH2:8][S:6][C:2]1[NH:1][CH2:5][CH2:4][N:3]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)CBr
Reactant: S=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)CSC1=NCCN1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 2-imidazolidinethione (1.02 g, 10 mmol), ethyl 3-bromopyruvate (1.95 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol), sodium iodide (10 mg), Adogen (200 mg) in N,N-dimethyl formamide (15 mL) was stirred at 20° C. for 15 hours under nitrogen. The reaction mixture was diluted with water and then extracted ethyl acetate. Organic phase was dried over sodium sulfate, evaporated, and chromatographed (silica gel, dichloromethane-methanol 9:1), giving the expected product, 3-(4,5-dihydro-1H-imidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, as a brown solid (1.8 g, 83%). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 4.36 (d, J=7.1 Hz, 2H), 4.25-4.00 (m, 3H), 3.57 (d, J=11.2 Hz, 1H), 3.50-3.35 (m 1H), 3.25-3.10 (m, 1H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:35][CH2:34]1>>[N:2]1([CH2:4][C@@H:5]2[CH2:6][C@H:7]([C:9]3[N:13]4[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]4=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:20]=4)[N:10]=3)[CH2:8]2)[CH2:1][CH2:35][CH2:34][CH2:3]1
Reactant: CN(C)CC1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Reactant: C1CCNC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1C[C@@H](CN2CCCC2)C1

Procedure:
Procedures for 3-(3-Dimethylaminomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine were followed, replacing dimethylamine with pyrrolidine, LC-MS (ES, Pos.): m/z 454 [MH+].