Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C1(P(=[CH:51][C:52]([O:54][CH3:55])=[O:53])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]=[CH:51][C:52]([O:54][CH3:55])=[O:53])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C=C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of oxalyl chloride (2.0M in methylene chloride, 9.60 mL, 19.2 mmol) in methylene chloride (100 mL) at −60° C. was added a solution of dimethyl sulfoxide (3.01 g, 38.6 mmol) in methylene chloride (10 mL) and the mixture was stirred for 5 min. A solution of (S)-(−)-1-(t-butoxycarbonyl)-2-pyrrolidinemethanol (3.08 g, 15.3 mmol) in methylene chloride (20 mL) was added dropwise over 5 min. After 30 min, triethylamine (12.8 mL, 91.8 mmol) was added and the reaction mixture was stirred at −60° C. for 15 min and then warmed to rt for a further 10 min. Water (50 mL) was added and the mixture extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude residue was dissolved in methylene chloride (100 mL) and treated with methyl (triphenylphosphoranylidene)acetate (1.4 eq). After 15 h the reaction mixture was concentrated and purified by silica gel chromatography to give the desired product (3.54 g, 90%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[OH:42][C@@H:43]([C:56]1[CH:61]=[CH:60][C:59](/[C:62](=[N:64]/O)/[NH2:63])=[CH:58][CH:57]=1)[CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][C@H:47]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:46]1>C(#N)C.C(OCC)(=O)C>[OH:42][C@@H:43]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[N:64]=[C:12]([C:9]3[C:8]([C:15]([F:18])([F:17])[F:16])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)[O:13][N:63]=2)=[CH:58][CH:57]=1)[CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][C@H:47]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:46]1
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(/C(N)=N/O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 2 h

Procedure:
5-Phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride, Int-II-D (78 mg, 0.3 mmol) was dissolved in acetonitrile (5 mL) and (S)-ethyl 1-((S)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate, Preparation 14B (100 mg, 0.298 mmol) was added. After 2 hours, 1M TBAF in THF (298 μL, 0.298 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting material was purified on a silica gel cartridge using an EtOAc/hexanes gradient to yield 67 mg of (S)-ethyl 1-((S)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate. MS (m+1)=557. HPLC Peak RT=3.32 minutes (Analytical Method A).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[C:11]1([C:17]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:23])[C:18](OCC)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([C:17]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:23])[C:18]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)c1ccccc1

Procedure:
A suspension of 3-quinuclidinol (5.1 g. 0.04 mole) and Na (~0.05 g.) in 20 ml. of toluene was heated to reflux in a flask equipped with a reflux head and stirrer. After the sodium reacted completely (about 15 minutes of refluxing), ethyl α-phenyl-α-phenylethynyl-glycolate (7.0 g., 0.025 mole) dissolved in 20 ml. of toluene was added very slowly over a two hour period. Towards the end of the addition a temperature drop of 6° was noted in the head and 10 ml. of the toluene-ethanol azeotrope slowly was distilled over. The reaction mixture was refluxed for an additional hour, and an additional 10 ml. of distillate was subsequently collected over a thirty minute period. The reaction mixture was poured on ice and acidified with 6N HCl. The toluene layer was separated and washed with several portions of 6N HCl. The combined water layers were neutralized with 10% NaOH, basified with potassium carbonate and extracted with chloroform several times. The chloroform layer was dried and subsequently stripped of volatile material in vacuo to leave a tacky solid. The material was washed with hot ether to give 5.2 g. (58%) of an off-white solid, m.p. 150°-90°. Recrystallization from benzene and then isopropanol yielded analytically pure material, m.p. 205°-8°.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11](F)[C:10]([F:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:16]([O:18][C:19]([N:21]([CH2:23][CH:24]1[O:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:22])=[O:20])[CH3:17].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:18][C:19]([N:21]([CH2:23][CH:24]1[CH2:25][N:26]([C:11]2[C:10]([F:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[C:12]=2[F:13])[CH2:27][CH2:28][O:29]1)[CH3:22])=[O:20])[CH3:17]
Reactant: CCOC(=O)N(C)CC1CNCCO1
Reactant: CCOC(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Yield: 71.8 %

Procedure:
A suspension of 22.2 g of ethyl 2,3,4,5-tetrafluorobenzoate, 22.2 g of 2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholine and 8.4 g of sodium hydrogen carbonate in 130 ml of acetonitrile is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 100 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the residue is puiified by chromatography on silica gel to give 29.0 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoate in 72% yield, as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH3:12][C:13]([CH2:15][CH3:16])=[O:14].[OH-].[K+].OS(O)(=O)=O>O.CO>[CH3:16]/[C:15](=[CH:10]\[CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])/[C:13](=[O:14])[CH3:12]
Reactant: CCC(C)=O
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)/C(C)=C/CC1CC=C(C)C1(C)C
Reaction time: 0.29 h
Yield: 60.4 %

Procedure:
152 G (1.0 M) of campholenic aldehyde having a purity of about 75% were added dropwise under stirring in 15-20 minutes to a mixture cooled at -5/-10° of 400 g (6.1 M) of methyl-ethyl ketone, 1025 g (35 M) of methanol, 30.5 g (0.54 M) of potassium hydroxide and 380 g of water. The mixture was kept at -5° for 24 hours, then at room temperature for the same period and neutralized thereupon with H2SO4 to 62.5%. After concentration under reduced pressure, the obtained residue was dissolved in 200 ml of water, diluted with petrol ether 30/50, washed until neutrality, dried and concentrated. 189.3 G of a raw material was thus obtained which on distillation with a Vigreux column of 15 cm length gave 144.6 g of (E)-3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-3-penten-2-one having a purity of 86% (yield 60.4%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH:13]([CH3:15])[CH3:14].[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[N+:24]=[N-:25].O>CN(C=O)C>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:23]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:25]=[N:24]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C(C)C
Reaction time: 0.25 h

Procedure:
DBU (3.6 ml; 24.07 mmol; 1.10 eq.) was dissolved in DMF (45 ml) and put under nitrogen atmosphere. Ethyl isobutyrylacetate (Aldrich, 3.807 g; 24.07 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (3 g; 21.858 mmol; 1 eq.) in DMF (10 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 5 hours. Water (80 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (2×100 mL). Combined organics were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a brown oil. It was used in the next step without further purification. LC/MS (Method B): 278.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20](C)C.Cl.CNC1CC1>CS(C)=O.O>[CH:23]1([N:19]([CH3:20])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC1CC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (750 mg, 3.14 mmol) in DMSO (5 ml) was added DIEA (812.7 mg, 6.29 mmol), N-methylcyclopropanamine hydrochloride (450 mg, 4.18 mmol) with stirring for 3 h at 75° C. in an oil bath. The resulting solution was diluted with water (200 ml), and the product was collected by filtration to give methyl 3-[cyclopropyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a solid (780 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3ccncc3)ccc21
Product: CC1c2ccc(-c3ccncc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].C(N(CC)CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH2:33][SH:34])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:34][CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2-Bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and triethylamine were combined in CH2Cl2. (3-trifluoromethyl-phenyl)-methanethiol was added, and the reaction was stirred at room temperature for at least 1 hour. After workup, the crude material was purified by silica gel chromatography.
Reaction SMILES: C1(C(=CC=CC=1)O)O.C(OC1C(=CC=CC=1)OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O:41][C:42]1[C:43](=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=1)[O:44]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[N+:57]([C:54]1[CH:53]=[C:43]([OH:44])[C:42](=[CH:56][CH:55]=1)[OH:41])([O-:59])=[O:58]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1OC(=O)c1ccccc1)c1ccccc1
Agent: O=C(Oc1ccccc1OC(=O)c1ccccc1)c1ccccc1
Agent: Oc1ccccc1O
Product: O=[N+]([O-])c1ccc(O)c(O)c1
Yield: 50 %

Procedure:
Further, the 3,4-dialkoxyanilines of formula I are obtained according to the invention in a yield of about 70% or more of the theoretical amount calculated on pyrocatechol whereas according to a known method comprising dibenzoylation of pyrocatechol, nitration of the pyrocatechol dibenzoate, hydrolysis 4-nitropyrocatechol dibenzoate, successive introduction of alkyl groups R1 and R2 into 4-nitropyrocatechol and reduction of 3,4-dialkoxy-nitrobenzene the 3,4dialkoxyanilines of formula I are obtained in a yield of less than 50% of the theoretical amount calculated on pyrocatechol.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@H:17]1[CH:22]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@H:17]1[CH2:22][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNCc1ccccc1
Reaction time: 15 h

Procedure:
Benzylamine (2.95 mmol, 1.2 eq) is added to a solution of (1S,2S,5R)-2-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.46 mmol, 1.0 eq) in chloroform (6.0 mL). After 10 min the mixture is treated with sodium triacetoxyborohydride (2.95 mmol), stirred for additional 15 h and poured into a sat. aq. NaHCO3 solution. The layers are separated and the aq. layer is extracted once with chloroform. The combined organic layers are washed twice with sat. NaHCO3 solution and water. The solvents are removed in vacuo and the residue is dissolved in ether (30 mL). Aq. HCl (0.1 M, 40 mL) is added, the layers are separated and the organic layer is extracted twice with aq. HCl (0.1 M, 30 mL each). The combined aq. layers are washed with ether (20 mL), made alkaline by addition of NaOH solution (1.0 M, 20 mL) and extracted three times with ether (40 mL each). The combined organic layers are dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.96 min; [M+H]+=303.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1.CC1(C)[O:33][CH2:32][CH:31]([CH2:34]O)[CH2:30][O:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NN=NN=C=NCC)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:34][CH:31]([CH2:32][OH:33])[CH2:30][OH:29])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: CC1(C)OCC(CO)CO1
Reactant: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1O
Agent: CCN=C=NN=NN=C=NCC
Agent: O=S(=O)(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
Toluene (0.4 ml) was added to 6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinolin-7-ol (compound 329) (20 mg) and (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (24 mg). Triphenylphosphine (43 mg) and a solution of diethylazocarbodiimide (29 mg) in toluene (0.2 ml) were added in that order to the mixture, and the mixture was stirred at room temperature for 4 hr. A 1 N aqueous sulfuric acid solution (1 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the mixture was washed with ethyl acetate, and the ethyl acetate layer was extracted with 1 N hydrochloric acid. Aqueous layers were combined, the combined aqueous layers were made alkaline by the addition of potassium carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (4.7 mg, yield 19%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17]Cl)[CH:16]=1.[H-].[Na+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([Br:10])[CH:16]=1)=[O:4]
Reactant: ClCc1cncc(Br)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a light yellow oil. MS: 299.2, 301.1 (M+H+).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=1>CN(C=O)C>[CH3:61][N:62]([CH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=1)[C:25]([C:22]1[CH:21]=[N:20][C:19]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:9]=[CH:8][C:7]([C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:6])=[CH:12][CH:11]=3)[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:27]
Reactant: CNCc1ccncc1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)O)cn3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)N(C)Cc4ccncc4)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 36.8 mg (0.1 mmol) (S)-2-{4-[4-(1-acetylamino-ethyl)-phenyl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid (XVII.1) and 51 μL (0.3 mmol) DIPEA in 2 mL DMF is added 38.0 mg (0.1 mmol) HATU and the mixture is stirred for 15 min at rt. Subsequent the mixture is added to 12.2 mg (0.1 mmol) methylpyridin-4-ylmethylamine and stirring is continued for 12 h. The solvent is removed in vacuo and the residue is purified using reversed phase column chromatography (water+0.1% NH4OH/MeOH) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:14][CH2:13][CH2:12][O:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: BrCCCCCCBr
Reactant: O=[N+]([O-])c1cccc(COCCO)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(COCCOCCCCCCBr)c1
Yield: 68.4 %

Procedure:
2-{(3-Nitrophenyl)methoxy}ethanol (6.50 g), 1,6-dibromohexane (24.2 g) and tetrabutylammonium bromide (0.21 g) were stirred under nitrogen at 200 and treated with 50% w/v sodium hydroxide (10 ml). The mixture was stirred vigorously for 19 h before water (150 ml) was added. The product was extracted with dichloromethane (3×80 ml) and the combined organic layer was dried (Na2SO4). Solvent evaporation in vacuo gave a residue that was purified by Biotage. Elution with PE-EtOAc (1:0 then 3:1) followed by solvent evaporation in vacuo gave the title compound (8.12 g). HPLC RT=3.238 min.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][C:47]=2[CH3:49])[NH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:52]([C:54]1[CH:61]=[CH:60][C:57]([CH2:58]Br)=[CH:56][CH:55]=1)[CH3:53].Cl>CN(C)C=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][C:47]=2[CH3:49])[N:42]([CH2:58][C:57]2[CH:60]=[CH:61][C:54]([CH2:52][CH3:53])=[CH:55][CH:56]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(CBr)cc1
Reactant: Cc1cccc2[nH]cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(C)cccc32)cc1
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-methyl-1H-indole (150 mg) in N,N-dimethylformamide (2 mL) was added 55% sodium hydride (12 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-ethylbenzyl bromide (55 mg) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with a mixed solvent of n-hexane and diethyl ether (10/1), and dried under reduced pressure to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-ethyl-benzyl)-4-methyl-1H-indole (139 mg). This material (125 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetra hydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give the title compound (58 mg).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:23]3[CH2:25][CH2:24]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NC1CC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 17 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (537 mg, 1.5 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (85 mg, 17%) which was obtained as a white solid after purification by chromatography (silica, 0 to 50% ethyl acetate in heptane). MS: m/e=330.4 [M+H]+.