Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[Br:22][CH2:23][CH2:24]Br.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH2:24][CH2:23][Br:22])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: BrCCBr
Reactant: COC(=O)C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL) was added dropwise a solution of n-butyl lithium (145 mmol, 58 mL 2.5M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of cyclopentane carboxylic acid methyl ester (100 mmol, 13.1 g) in THF (20 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 1,2-dibromoethane (90 mmol, 16.91 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (200 mL) and the organic compound was extracted into ether (2×100 mL). The combined extracts were washed with a saturated solution of sodium chloride (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 95-105° C./2.5 mm Hg to obtain 11.5 g (49%) of a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[S:18])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3]1.[CH2:25]([Cl:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[Cl-:32].[CH2:25]([S:18][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)=[CH:7][N+:2]([CH3:1])=[CH:3][C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1cc(-c2ccccc2)c(=S)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: ClCc1ccccc1
Solvent: c1ccccc1
Product: C[n+]1cc(-c2ccccc2)c(SCc2ccccc2)c(-c2cccc(C(F)(F)F)c2)c1
Product: [Cl-]

Procedure:
A mixture of 2.0 g. of 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinethione and 10 ml. of benzyl chloride in benzene was heated under reflux for 6 hours. The mixture was cooled and the benzene was removed in vacuo. The residue was put on a silica gel column in benzene and the column was flushed with benzene. The product was then removed from the column with denatured ethanol. The ethanol was removed and the residue was crystallized from ether yielding 0.7 g. of 4-benzylthio-1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)pyridinium chloride, m.p. 70°-73°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:11]#[N:12].[Na+].[NH4+:14].[Cl-].N.CO.N>CO>[NH2:14][CH:9]([C:11]#[N:12])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=CCCN1CCCCC1
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N#CC(N)CCN1CCCCC1

Procedure:
The above aldehyde (1 equiv) is mixed with NaCN (1.1 equiv), NH4Cl (1.1 equiv) are mixed together in 2 Molar NH3/MeOH (4 equiv NH3). The flask is fitted with a reflux condenser and the mixture is refluxed. At the end of each of the first 3 h an additional equivalent of NH3 in MeOH is added. The reaction mixture is cooled and the excess solids are filtered away on a frit. The filtrate is concentrated by rotary evaporation and the residue is triturated with diethyl ether and the mixture is filtered again. The filtrate is concentrated on a rotovap. The product is purified, if necessary, by flash chromatography on silica with EtOAc/hexanes as an eluent to yield 1-amino-1-cyano-3-(piperid-1-yl)-propane.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:38]1C=CC=C1CC(O)=O.[CH3:47][CH:48]([O:50]C(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:48]([S:38][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:50])[CH3:47]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CSC(C)=O)cc(C(=O)OCC)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To diethyl 5-(hydroxymethyl)isophthalate (2.52 gm, 10 mmol) in THF (30 ml), triphenyl phosphine (5.25 gm, 20 mmol) was added followed by thiolacetic acid (1.52 gm, 20 mmol) and Diisopropylazodicarboxylate (4.04 gm, 20 mmol) at 0° C. Reaction mixture was then allowed to come to rt and stirred for 2 h. Then solvent was removed, crude was redissolved in minimum amount of CH2Cl2. With stirring, hexane was added and the resultant solids were discarded. Filtrtae was evaporated to dryness and the residue was column purified to yield diethyl 5-(acetylthiomethyl)isophthalate in 95% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:34])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1
Reactant: CCOC(=O)c1cnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3n2COC)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3n2COC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of ethyl 2-{1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-5-carboxylate (2.19 g), methyl iodide (0.57 mL), potassium carbonate (0.95 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (2.18 g, yield 97%) as pale-yellow crystals. melting point 142-143° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Mg].II.[CH2:12]([N:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(I)C.C1C=CC=CC=1.CCOCC>[CH2:12]([N:19]1[CH2:20][CH2:21][C:22]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([O:26][CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCBr
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCI
Product: CCCCCCCC1(OCCO)CCN(Cc2ccccc2)CC1

Procedure:
A solution of 101.5 g of n-heptyl bromide in 300 ml was added over 1 hour under a nitrogen atmosphere to a flask containing 9.6 g of magnesium turnings, 50 ml of ether, 3 drops of ethyl iodide and an iodine crystal and the mixture was stirred for 1 hour. A solution of 46.6. g of 8-benzyl-1,4-dioxa-8-azaspiro [4,5] decane in 1 liter of anhydrous benzene was added to the resulting solution and after removal of the ether, the mixture was refluxed for 16 hours. The solution was then cooled and 20 ml of water followed by 400 ml of a saturated aqueous ammonium chloride solution was added with stirring. The organic phase was decanted and the solvent was distilled under reduced pressure. The residue was rectified to obtain 40 g of 2-(1-benzyl-4-heptyl-4-piperidyloxy)-ethanol as an oil distilling between 150° to 200° C. The oil was used as is for the next step.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[CH2:28]([NH2:30])[CH3:29]>CN(C)C(=O)C>[CH2:28]([NH:30][CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1)[CH3:29]
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCN
Solvent: CC(=O)N(C)C
Product: CCNC/C=C/[C@H]1CC[C@H](CCN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with ethylamine in N,N-dimethylacetamide at room temperature to yield trans-N-{2-[4-(3-ethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 433 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]([CH3:35])[C:26]([CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:27][N:28]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]([CH3:35])[C:26]([CH2:29][N:30]([CH2:31][CH2:32][O:33][CH3:34])[S:38]([CH3:37])(=[O:40])=[O:39])=[CH:27][N:28]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)n1C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a suspension of the amine 348 (61 mg, 0.119 mmol) in DCM (5 ml) was added methanesulfonyl chloride (20.53 mg, 1.5 eq, 0.179 mmol) and iPr2NEt (46.3 mg, 3 eq, 0.358 mmol) and the reaction mixture was stirred at RT for 3 hours. The mixture was diluted with EtOAc then washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic phase was collected, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent 25% MeOH in EtOAc) to afford the desired compound 349 as a pale yellow solid (34 mg, 48%). 1H NMR (d6 DMSO) 8.27 (s, 1H), 8.10 (d, J=5.48 Hz, 1H), 7.53 (s, 1H), 7.25 (m, 1H), 6.95 (t, J=9.0 Hz, 1H), 6.76 (m, 1H), 6.71 (s, 1H), 6.24 (d, J=5.48 Hz, 1H), 6.14 (s, 1H), 4.06 (s, 2H), 3.49 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H), 2.12 (m, 3H), 0.23 (m, 2H), 0.00 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][CH2:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:53]4[CH2:54][CH2:55][CH:50]([CH2:49][O:48][CH3:47])[CH2:51][CH2:52]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: COCC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCC(COC)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-(methoxymethyl)piperidine (Alfa) to give the title product. LC-MS (ES+) 776 [(M+H)+].
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.C(#N)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:27]1([S:33]([NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCOc1cccc2nccn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: O=S(=O)(NCCCOc1cccc2nccn12)c1ccccc1
Yield: 59.4 %

Procedure:
To a suspension of 5-[3-(amino)propyloxy]imidazo[1,2-a]pyridine dihydrochloride (2.64 g, 10 mmoles) and triethylamine (4.88 ml, 35 mmoles) in methylene chloride (100 ml)-acetonitrile (30 ml) was added benzenesulfonyl chloride (1.53 ml, 12 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for hour. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the crude product thus obtained was recrystallized from methylene-ethanol to obtain 1.97 g of the desired product (59.5%, light brown crystals).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[Cl:9][C:10]1[C:15]([NH2:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>COCCOC.C(Cl)Cl.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.[Cu]I>[Cl:9][C:10]1[C:15]([NH2:16])=[C:14]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:13]=[CH:12][N:11]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1c(Cl)ncnc1C#Cc1ccccc1
Temperature: 25 °C
Yield: 22 %

Procedure:
Ethynylbenzene (0.092 mL, 0.92 mmol) was added to a solution of 4,6-dichloropyrimidin-5-amine (100 mg, 0.61 mmol), Pd(PPh3)4 (140 mg, 0.12 mmol), CuI (116 mg, 0.61 mmol) and DIPEA (0.5 mL, 3.05 mmol) in DME (6.1 mL). The reaction mixture was stirred in the dark over night at room temperature, diluted with DCM, washed sequentially with dilute aqueous citric acid and water, dried over anhydrous Na2SO4 and concentrated under reduce pressure. The residue was purified by flash chromatography, eluent EtOAc/hexane (1:3), to afford title compound 251 (30.8 mg, 22% yield) as a yellow solid. MS (m/z): 230.1 (100.0%), 232.1 (33%) (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.O[C:23]1[CH:27]=[CH:26][O:25][N:24]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:25]1[CH:26]=[CH:27][C:23]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[C:11]([F:21])[CH:10]=3)[CH2:4]2)=[N:24]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCOCC2)c(F)c1
Yield: 69.2 %

Procedure:
Prepared by the general method of Example 1 using as starting material 5(R)-hydroxymethyl-3-(4-morpholino-3-fluoro-phenyl)oxazolidin-2-one (WO95/07271; 300 mg, 1.01 mmol), 3-hydroxyisoxazole (95 mg, 1.12 mmol), diisopropylazodicarboxylate (225 mg, 1.11 mmol) and triphenylphosphine (305 mg, 1.16 mmol) in THF (5 ml). Purified by flash chromatography (Merck 9385 silica. EtOAc/isohexane (7/3)) to give the title compound (254 mg, 69%) as a colourless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[C:12]([Cl:19])=[N:13][C:14](Cl)=[CH:15][C:16]=1[Cl:17].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.P([O-])(O)(O)=O.[Na+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[C:12]([Cl:19])=[N:13][C:14]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:15][C:16]=1[Cl:17]
Reactant: c1nc[nH]n1
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-n2cncn2)nc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.42 g (11.0 mmol) of 60% sodium hydride in paraffin was added a little at a time to 3.00 g (9.6 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine and 0.70 g (9.6 mmol) of [1,2,4]triazole dissolved in 30 ml of dimethylformamide. The mixture was stirred at room temperature for 3 d, added to 50 ml of sodium dihydrogenphosphate solution, extracted three times with in each case 50 ml of methyl tert-butyl ether, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel using cyclohexane/ethyl acetate. Yield 1.5 g of a colorless solid of m.p. 210° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:27]([OH:28])=[C:26]([O:29][CH3:30])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33].N(S([O-])(=O)=O)(S([O-])(=O)=[O:37])[O].[K+].[K+].O.P(O)(O)([O-])=O.[K+]>CN(C)C=O.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:27](=[O:28])[C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24](=[O:37])[C:23]=1[CH3:33]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1080 h
Yield: 54.9 %

Procedure:
To a solution of 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methylphenol (2.3 g) in dimethylformamide (1.5 l) are added potassium nitrosodisulfonate (30 g), water (1.5 l), methanol (300 ml) and monopotassium phosphate (1.3 g) and the mixture is stirred at room temperature for 45 days. The reaction mixture is extracted with dichloromethane and recrystallized from ether. The above procedure gives 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.3 g) as yellow needles. Melting point: 85° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C@H:30]([C:39](OC)=[O:40])[CH2:31][S:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:25]([N+:43]([O-:45])=[O:44])[CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:13][CH:12]=2)=[C:7]([O:46][CH3:47])[CH:6]=1.[Li+].[BH4-]>C1COCC1>[OH:40][CH2:39][C@@H:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]=3[O:46][CH3:47])=[CH:12][CH:13]=2)=[O:18])(=[O:22])=[O:21])=[CH:24][C:25]=1[N+:43]([O-:45])=[O:44])[CH2:31][S:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(CCCO)cc3OC)cc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCCO)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CO)CSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 2 h

Procedure:
A solution of Example 133D (300 mg, 0.38 mmol) in THF (4 mL) at room temperature was treated with 2M LiBH4 in THF (470 μL, 2.5 eq), stirred for 2 hours, quenched with a drop of water, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide the desired product. MS (ESI(−)) m/e 650 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 1.75 (m, 2H), 2.65 (t, 2H), 3.32 (m, 4H), 3.43 (t, 2H), 3.61 (dd, 1H), 3.72 (dd, 1H), 3.77 (s, 3H), 4.06 (m, 1H), 6.88 (d, 1H), 6.96 (s, 1H), 7.11 (m, 2H), 7.22 (m, 2H), 7.31 (m, 2H), 7.59 (m, 2H), 7.88 (m, 3H), 8.10 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20].[CH2:21]=O>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:16][C:10]=2[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: C=O
Reactant: O=C1c2ccoc2CCN1Cc1ccccc1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(Cc1ccccc1)C2=O

Procedure:
To a solution of 0.181 g (0.796 mmol) of 5-benzyl-6,7-dihydro-5H-furo[3,2-c]pyridin-4-one in 10 ml of acetic acid, 0.36 g (4.0 mmol) of 50% aqueous dimethylamine and 0.32 g (4.0 mmol) of 37% aqueous formaldehyde were added, followed by refluxing for 6 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@H:31](O)[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][C@H:31]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: O[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (250 mg, 0.81 mmol) was added to a solution of Intermediate 26a (150 mg, 0.67 mmol) and Et3N (101 mg, 1.00 mmol) in DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (220 mg, 86%). LCMS (Method 4): Rt 4.15 min, m/z 379 [MH+].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:27]>C1COCC1.CN(C=O)C.O>[CH2:1]([N:8]([CH3:27])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CCNCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
At 0° C., a solution of tert-butyl 4-(2-(benzylamino)ethyl)piperidine-1-carboxylate (400 mg, 1.25 mmol, 1 eq) in THF (10 ml) was added dropwise to a suspension of NaH (110 mg, 2.74 mmol, 1.3 eq, 60% in mineral oil) in DMF (4 ml), and stirring was carried out for 30 min. Then a solution of iodomethane (93 μl, 1.5 mmol, 1.2 eq) in THF (2 ml) was added dropwise at 0° C., and stirring was carried out for 2 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 60% ethyl acetate in hexane), a light-yellow solid was obtained. Yield: 34% (140 mg, 0.42 mmol).