Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.N1C=CC=CC=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1)([O-:25])=[O:24]>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:35][CH2:34][CH2:33][NH:32][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Solvent: COCCOCCOC
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NCCNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 165 °C
Yield: 55 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4,6-dimethyl-pyridin-2-yl ester (prepared according to J. Org. Chem., 63, 10048-51, 1998), using pyridine as base. 0.6 g, 2.35 mmol) in diglyme (2 mL) was added N*1*-(4-nitro-phenyl)-ethane-1,2-diamine (0.51 g, 2.82 mmol). The reaction mixture was heated to 165° C. for 24 h. The resulting reaction mixture was concentrated under reduced pressure and the residue diluted with chloroform. The organic layer was washed with brine and water and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 mesh) using 20% ethyl acetate/petroleum ether as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-ethane-1,2-diamine (0.38 g, 55%) as a cream solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH2:11][CH2:12]O)[CH:8]=[CH2:9].C([O-])(O)=O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOCCO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCCOC(=O)C(=C)C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A three-necked flask equipped with stirrer, thermometer, reflux condenser and Dean-Stark trap is charged with methacrylic acid (137.7 g, 1.6 mol), ethylene glycol monoallyl ether (80.7 g, 0.8 mol), p-toluenesulfonic acid (0.76 g, 4.0 mmol) and toluene (650 mL). After allowing the reaction to proceed at 120° C. for 5 hours, 0.12 g of p-toluenesulfonic acid is added, and the reaction is further allowed to proceed at the same temperature for 6 hours. Then, 0.1 g of p-toluenesulfonic acid is added, and the reaction is further allowed to proceed at the same temperature for 9 hours, whereupon the reaction is completed. During the whole reaction period, methacrylic acid and ethylene glycol monoallyl ether are monitored with liquid chromatography. The final conversion amounted to 98%. The reaction mixture is neutralized by adding an aqueous solution of NaHCO3 and allowed to separate into two layers. The aqueous layer is extracted once with toluene. The combined organic layer is dried over CaCl2 and the volatile matter is distilled off under reduced pressure. The crude product is distilled under reduced pressure (60, 2 mmHg) to give 98.7 g (73% yield) of 2-allyloxyethyl methacrylate shown below.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH:46]=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]([CH:46]=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 80.4 %

Procedure:
To a solution of 5-n-propyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxaldehyde (4.05 g, 6.6 mmol) in THF (25 ml) was added 4N HCl (11 ml) with stirring. The mixture was stirred at room temperature for 5 hours. The THF was removed by rotary evaporation and the residue was adjusted to pH 5-6 with 4N NAOH (~10 ml). The product was extracted into EtOAc (2×50 ml), the organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography of the reddish solid residue (1.97 g) on silica gel (30 g; EtOAc/hexanes, 1/1) gave 1.4 q of the title compound as a pale pink solid; m.p. 68-71° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].[CH3:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:24](Cl)=[O:25])[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=1)(=[O:13])=[O:12]>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:24]([C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][CH3:9])[CH:15]=1)=[O:25]
Reactant: CN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NCC3CCCN3C)c1)OCCO2
Yield: 77 %

Procedure:
In a similar manner to that of the above example, 71 g of levorotatory 1-methyl-2-aminomethyl-pyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 175 g of levorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 187°-187.5° C.; yield: 77%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>>[Br:1][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: BrBr
Product: O=C(O)C(Br)c1ccc(Cl)cc1

Procedure:
In a stirred reactor with reflux condenser (connected to a caustic scrubber) 171 g 4-chlorophenyl acetic acid are pre-charged in 400 g chlorobenzene and heated to 105° C. Within 30 minutes 42 g thionyl chloride is added at 105-110° C. to form partly the acid chloride. To the reaction mixture 256 g bromine (1.6 mole) are added within 90 minutes at 105-108° C. The reaction mixture is stirred for another 2-3 hour at 105-108° C. until the conversion of the 4-chlorophenyl-acetic acid is complete (control by HPLC). Excess bromine is distilled off as a bromine/chlorobenzene mixture at 90° C. until a vacuum of 250 mbar is reached and the colour of the reaction mixture has changed from brown to yellow. The bromine distillate can be re-used in the next batch. The reaction mixture, containing a mix of bromo-(4-chloro-phenyl)acetic acid and acid chloride is diluted with chlorobenzene to a weight of 800 g and can directly be converted to (4-chloro-phenyl)-prop-2-ynyloxy-acetic acid according to Example 14.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CC(N(C)C)=O.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (2.0 g, 10.58 mmol) was dissolved in dimethyl acetamide (35 mL), morpholine (2.88 mL, 31.73 mmol) was added thereto, and the mixture was subjected to a reaction at 145° C. for 19 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic layer was washed with an aqueous sodium hydrogen carbonate solution (50 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (10 mL) and n-hexane (80 mL) to obtain the title compound as a brown solid (2.1 g).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][NH:3]1.O=S(Cl)[Cl:21]>CN(C=O)C>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Temperature: 80 °C

Procedure:
A mixture of the compound of formula (IX) (3 g, 12 5 mmol), SOCl2 (30 mL) and one drop of DMF was heated at 80° C. until the reaction was complete (TLC analysis). The volatile components were evaporated (including SOCl2) to provide crude compound of formula (Xa) that was purified by column chromatography (eluting with EtOAc/DCM, 1:8, v/v) to give free base of the compound of formula (Xa). The compound of formula (Xa) 1H NMR (300 MHz, d6-DMSO): δ 7.53 (d, J=3.3 Hz, 1H), 7.68 (d, J=3.3 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.90 (s, 1H), 9.64 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[NH:8][C:7]1=[S:16])[CH2:4][CH3:5].[CH3:17]I>O1CCCC1>[CH3:17][S:16][C:7]1[N:6]([CH2:3][CH2:4][CH3:5])[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: CI
Reactant: CCCn1c(=S)[nH]c2ccsc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(SC)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a sulfonation flask, 0.84 g (0.021 mol) of a ˜60% sodium hydride dispersion is added to 20 ml of absolute tetrahydrofuran, and then 4.8 g (0.021 mol) of 3-propyl-2-thioxo-2,3-dihydro-1H-thieno-[3.2-d]pyrimidin-4-one, dissolved in 80 ml of tetrahydrofuran, are added dropwise such that the internal temperature remains constant at about 25° C. The mixture is stirred for 1 hour at room temperature and then 4.3 g (0.03 mol) of methyl iodide are added all at once. The mixture is refluxed for 4 hours and then the tetrahydrofuran is removed in a water-jet vacuum. The residue is taken up in ethyl acetate and the organic phase is extracted three times with water. The organic phase is dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the crude product which is purified by column chromatography over silica gel (eluant: ethyl acetate/hexane 1:3). 2-Methylsulfanyl-3-propyl-3H-thieno[3.2-d]pyrimidin-4-one is obtained in virtually quantitative yield and having a melting point of 142-144° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(F)c(F)c1
Product: Fc1ccc(OCCCBr)cc1F

Procedure:
Analogously to Example 91b, 2.00 g of 3,4-difluorophenol and 31.0 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.66 (1:6 EtOAc-heptane); Rt=5.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[Si:13]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 1400 g (8.1 mol) of 3-bromophenol, 1218 g (8.1 mol) of tert-butylchlorodimethylsilane and 1376 g (20.2 mol) of imidazole in 1600 mL of N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into pH 8 aqueous buffer solution and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give 2314 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as an orange oil. NMR (CDCl3, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[OH:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: COc1ccc(CONC(=O)C(CC(C)C)CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide (220 mg) in dichloromethane (4 ml) was added trifluoroacetic acid (200 μl) and triethylsilane (145 μl). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue was purified on silica gel (eluant:dichloromethane-ether-methanol (8.0:20:0.5) to dichloromethane-methanol (80:20) to give the title compound (88 mg, 56%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]([CH2:22][CH2:23][O:24]C(=O)C)[CH2:5]1)(=O)C.[OH-].[Na+]>CCO.O>[OH:24][CH2:23][CH2:22][CH:6]1[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[C:10]([CH3:20])=[CH:9][C:8]=2[CH3:21])[NH:4][CH2:5]1
Reactant: CC(=O)OCCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Temperature: 60 °C
Reaction time: 10 h
Yield: 51.6 %

Procedure:
N-[1-Acetyl-3-(2-acetoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (4.0 g) was dissolved in EtOH (40 ml) and a solution of NaOH (2.2 g) in water (10 ml) was added, which was followed by stirring at 60° C. for 10 hr. EtOH was evaporated under reduced pressure, and CHCl3 (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 1.6 g of N-[3-(2-hydroxyethyl)-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH:15](OCC)=[O:16].[H-].[Na+]>COCCOC>[CH:15]([CH:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:16]
Reactant: CCOC(=O)CCc1ccc(C)nc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(C)nc1

Procedure:
Ethyl 3-(6-methyl-3-pyridyl)propionate was reacted at 0° with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give ethyl 2-formyl-3-(6-methyl-3-pyridyl)propionate, m.p. 142°-144°, which was heated under reflux with dried nitroguanidine and sodium methoxide in methanol to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone, m.p. 215°-6° (decomp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CN(C)C=O
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 0.17 h

Procedure:
To a 50 mL beaker was added about 1 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole to 30 mL of dimethylformamide (DMF). Additional (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the resulting solution until a suspension of the material was formed. The solution was stirred for approximately 10 minutes, and then filtered through a 0.45 μm Poly(tetrafluoroethylene) (PTFE) or Nylon filter. The resulting saturated solution was placed in a shallow petri dish, covered and stored under refrigerated conditions (approximately 5° C.) with a humidity range of about 0 to 50 percent until crystals formed (between 4-6 days). The identity of the title compound is confirmed by single crystal x-ray diffraction and Raman spectroscopy, and shown to contain between about 96 and 98 percent (w/w) of the 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 2 and 4 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H-benzimidazole.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>CC#N>[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(CO)n1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(COc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 70 °C
Yield: 61.5 %

Procedure:
To 35 mL CH3CN was added (6-Methyl-pyridin-2-yl)-methanol (3.5 g, 28.4 mmol), followed by potassium carbonate (17.9 g, 129.6 mmol), and 2-Chloro-1-fluoro-4-nitrobenzene (6.48 g, 36.9 mmol). The suspension was stirred and heated at 70° C. for 30 h, after which time the bright yellow mixture was allowed to cool to rt. The contents were cooled to rt, filtered, and washed with CH2Cl2. The filtrate was concentrated in vacuo to a a light yellow solid which was triturated with Hex/EtOAc (5:1), yielding 2-[(2-chloro-4-nitrophenoxy)methyl]-6-methylpyridine (4.87 g, 61%) as a white solid.
Reaction SMILES: CN(C)C(=O)C.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([NH:30][CH3:31])[C:27]([NH2:32])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[NH:32][C:12](=[O:13])[C:8]([CH3:15])([CH3:7])[C:9](=[O:10])[N:30]([CH3:31])[C:28]=2[CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CNc1cc(OCc2ccccc2)ccc1N
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reaction time: 4 h
Yield: 57.8 %

Procedure:
Under ice cooling, a N,N-dimethylacetamide (3 mL) solution of dimethylmalonic acid dichloride (0.68 g, 4.0 mmol) was added dropwise to a N,N-dimethyl acetamide (5 mL) suspension of 5-benzyloxy-N1-methylbenzene-1,2-diamine 1/2 sulfate (1.11 g, 4.0 mmol). After the reaction solution was stirred at the same temperature for 4 hours, water (8 mL) was added. The mixture was stirred at 10° C. or less for 30 minutes, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 60° C., thereby obtaining 0.75 g of a slightly pink, powdery target compound (yield: 57.8%).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:19]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(N)C(=O)O
Reactant: CCCCCCCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of Example 4A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl chloride and 30.12 g (0.185 mol) of octanoyl chloride. The product crystallizes from toluene/n-hexane.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
To 7-azaindole 1 in dichloromethane was added 6-chloronicotinoyl chloride 8, followed by aluminum chloride, under an atmosphere of nitrogen at −10° C. The reaction was stirred and allowed to warm to room temperature overnight. The reaction was quenched with 3 N hydrochloric acid and concentrated hydrochloric acid was added until all solids dissolved. The mixture was extracted with dichloromethane and the combined organic portions were dried with magnesium sulfate, filtered, and the filtrate was concentrated. The resulting solid material was recrystallized from chloroform/hexane to provide (6-Chloro-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 and used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:9]>O=[Mn]=O>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: O
Agent: O=[Mn]=O
Product: NC(=O)c1cccnc1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
0.096 mole 3-cyanopyridine was dissolved in 4.55 mole of water and 0.0115 mole of MnO2 prepared by above method was added to this. The mixture was refluxed at 100° C. for 13.5 hrs. The reaction mixture as cooled and filtered. The filtrate was evaporated to dryness to get solid nicotinamide 0.0879 mole. Yield of nicotinamide was 91.56 mole %.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1
Reactant: CO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
25 g (0.13 mol) of (E)-4-hydroxy-3-methoxycinnamic acid were dissolved in 180 ml of methanol, and 5 ml of concentrated sulphuric acid were added. The solution was heated under reflux for 2 hours. The main amount of the methanol (about 150 ml) was then distilled off and the residue that remained was poured into 500 ml of ice-water. The precipitated ester was filtered off with suction, washed in succession with cold water, with a small amount of a cold saturated sodium bicarbonate solution and again with cold water and dried at 50° C. under a waterjet vacuum. Chromatography on 250 g of silica gel using dichloromethane/diethyl ether (19:1) yielded 21.78 g of (E)-4-hydroxy-3-methoxycinnamic acid methyl ester in the form of a light-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.750 g, 4.00 mmol) in DCM (10 mL) was cooled to 0° C. and charged with triethylamine (0.67 mL, 4.8 mmol), methanesulfonyl chloride (0.34 mL, 4.4 mmol), and 4-dimethylaminopyridine (0.005 g, 0.04 mmol) and stirred at ambient temperature for 6 h. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 2.05-2.36 (m, 2H), 3.05 (s, 3H), 3.43-3.74 (m, 4H), 5.24-5.30 (m, 1H).