Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH3:12]>[Pd].CO>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cccc1F
Reaction time: 27 h

Procedure:
A mixture containing 1-fluoro-2-methoxy-3-nitrobenzene (36.30 g, 0.21 mol), palladium on carbon (10% w/w, ˜8 g), and methanol (200 mL) is stirred under an atmosphere of hydrogen (1 atm) for 27 h. The mixture is filtered and the resulting solution is evaporated to dryness under reduced pressure to give 11 as a brown oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 3.75 (br, 2H, NH2), 3.91 (d, JH-F=1.5 Hz, 3H, OCH3), 6.46 (m, 2H, overlapping H-4 and H-6), 6.79 (apparent t of d, JH-H=8.0 Hz, JH-F=5.5 Hz, 1H, H-5). 19F{1H} NMR (CDCl3): δ −132.5 (s). 13C{1H} NMR (CDCl3): δ 60.7 (d, JC-F=5.0 Hz, OCH3), 106.1 (d, JC-F=19.5 Hz, C-4), 110.9 (d, JC-F=2.5 Hz, C-6), 123.7 (d, JC-F=9.5 Hz, C-5), 134.9 (d, JC-F=13.0 Hz, C-2), 141.3 (d, JC-F=5.0 Hz, C-1), 154.4 (d, JC-F=244.0 Hz, C-3). LCMS m/z calcd for C7H8FNO ([M]+) 141. Found 142 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C(=O)=O.[Li]CCCC.[C:20]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.9 %

Procedure:
A solution of 1-bromo-2-(trifluoromethyl)benzene (0.5 g, 2.222 mmol) in anhydrous THF (10 mL) was cooled to −78° C. (dry ice WA bath) under argon atmosphere. BuLi (2.5 M in hexanes, 1.068 mL, 2.67 mmol) was added in drops with efficient stirring. The reaction mixture was stirred at −78° C. for 40 min. A solution of cyclopentanone (0.243 g, 2.89 mmol) in anhydrous THF (1.5 mL) was added slowly (in drops) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, gradually brought to room temperature, and stirred for 1 h. The reaction mixture was cooled by an ice bath, quenched with water, and acidified to pH 4-5 by addition of concentrated HCl. The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water (2 times), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as an oil (250 mg). LCMS m/z=213.1 [M−H2O+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:15])[C:10]=1[S:11](Cl)(=[O:13])=[O:12])=[O:5])[CH3:2].[O-:16][C:17]#[N:18].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH2:30])[N:23]=1.S(=O)(=O)(O)O>C(#N)C.ClCCl.N1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:17]([NH:18][S:11]([C:10]2[N:9]([CH3:15])[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:16])[N:23]=1
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)Cl
Reactant: N#C[O-]
Reactant: COc1cc(OC)nc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
2.603 g of 4-ethoxycarbonyl-1-methylpyrazole-5-sulfonylchloride was dissolved in 20.0 ml of acetonitrile. To the resulting solution were added 0.715 g of sodium cyanate and 1.552 g (10.0 mM) of 4,6-dimethoxy-2-aminopyrimidine with stirring. The reaction mixture was maintained at 40° C. for about 10 minutes and then 0.396 g of pyridine was added dropwise thereto over 5 minutes via a syringe. While maintaining the temperature of 40° to 45° C., the reaction mixture was continuously and vigorously stirred for 3 hours to complete the reaction. After the reaction was completed, the reaction mixture was adjusted to pH 4 by adding 5% aqueous sulfuric acid solution and dichloromethane to extract the reaction product. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The organic solvent was removed from the filtrate to obtain 4.103 g (Yield 99%) of the title compound in the solid state.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:21].CCCCOCCO>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCOCCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12

Procedure:
A 14.0 g amount of 4-amino-1,5-naphthalenedisulfonic acid is suspended in 100 ml of water and the solution is made basic with 5 N sodium hydroxide. The solution is warmed and absolute ether alcohol is added until a solid is precipitated. The solid is collected by filtration and is washed with 85% aqueous ethyl alcohol, ethyl alcohol and ether, then dried in vacuo to yield 12.0 g of 4-amino-1,5-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(CO)ccc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of methyl-4-bromo-3-methylbenzoate (4.31 g) in dry tetrahydrofuran (20 ml) was stirred and cooled to 0° C. under nitrogen gas. A solution of 1.5M diisobutylaluminium hydride in toluene (44 ml) was added slowly and the reaction stirred for 2.5 hours, then quenched with methanol and allowed to warm to 21° C. Silica was added and the reaction concentrated in vacuo and purified using SPE (Si cartridge) using cyclohexane:ethyl acetate (3:1) as an eluent which furnished the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13].C1C(=O)N([Br:30])C(=O)C1>C1(C)C=CC=CC=1.CN(C)C=O.[Cl-].[Na+].O>[Br:30][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][CH:21]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Yield: 75.9 %

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (3.30 g, 10 mmol, Example 1) and NBS (1.869 g, 10.50 mmol) were heated at 110° C. for 2 hr in Toluene (50 ml) and N,N-dimethylformamide (DMF) (10 ml). The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). Very bad emulsions were obtained that did not clear using brine, filteration or saturation with salt. Repeated extractions with ethyl acetate (×10) and treatment of the organic extracts with anhydrous sodium sulfate removed the water. The solvents were concentrated in vacuo, and the residue dissolved in chloroform (500 mL), dried over anhydrous sodium sulfate and concentrated to an oil. The crude oil was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% gradient of [10% 2M NH3/MeOH in DCM]/DCM) to afford product 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (3.1 g, 7.59 mmol, 76% yield), as a beige foam. A 0.180 g sample of this material was further purified by mass-directed automated preparative HPLC and then dissolved in dichloromethane (5 ml) and treated with 4N HCl in dioxane (0.5 ml). The solvents were removed in vacuo and the resulting solid tritruated in diethyl ether to afford 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (0.095 g, 0.213 mmol, 2.135% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[C:18]([BH3-])#[N:19].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 1-benzyl-4-piperidone (XXV, Chart G, 24.5 mL, 0.1295 mol), N-methylamine hydrochloride (44.75 g, 0.6628 mol) and methanol (50 ml) is stirred for 35 minutes at 20-25°, at which time additional methanol (10 ml) is added. The mixture is then cooled in an ice bath and a solution of sodium cyanoborohydride (9.1749 g, 0.1460 mol) in methanol (68 ml) is added to the mixture. The mixture is stirred for 5 min and then is allowed to warm to 20-25°. After 1.25 hr the mixture is concentrated under reduced pressure and saturated aqueous sodium bicarbonate is added. After stirring for 1 hr, the mixture is extracted with dichloromethane and the organic phases are combined, backwashed with saline, dried with magnesium sulfate and concentrated under reduced pressure to give (XXVII). The material is upgraded by forming the dihydrochloride salt and collecting the resulting solids. The dihydrochloride salt is further upgraded by trituration with dichloromethane. The free base (XXVII) is recovered by slurrying the dihydrochloride salt (7.5204 g, 0.02713 mol) in dichloromethane and adding enough saturated sodium bicarbonate to dissolve all the solids and then extracting the aqueous layer exhaustively with dichloromethane to obtain N-(1-benzylpiperidin-4yl)-N-methylamine (XXVII), MS (m/z) 204; IR (neat) 2942, 2796, 2775, 743 and 2749 cm-1.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>C(OCC)C.CCCCC.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH:2]([CH:3]1[CH2:4][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH2:1]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CC=C
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: C=CC1CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Butadiene (200 ml, Aldrich) condensed at -700 was transferred to a glass lined autoclave vessel and ethyl diazoacetate (20 g, 0.175 mol, Aldrich) and rhodium acetate dimer (0.3 g, Aldrich) added. The suspension was stirred in a sealed autoclave for 24 hours at ambient temperature. The contents were diluted with 2% diethyl ether in pentane and passed through a silica pad (50 g). The pad was washed with a little ethanol and further ether-pentane. The eluant containing ethanol was treated separately. The organic phases were concentrated at reduced pressure (<5°) and subjected to short path bulb to bulb disillation (90-105° at 12 mm) to give the product as a colourless liquid (14.6 g).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[C:8]([F:29])[C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.N12CCCN=C1CCCCC2>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[C:8]([F:29])[C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4.5 g of ethylamine are added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 7.1 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 100 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 1 hour and a half. After cooling to a temperature close to 20° C., the product is drained and washed with twice 30 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-tri fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a cream solid melting at 284° C., which is used for the subsequent steps without further purification.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:14][C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[BH4-].[Na+]>C1COCC1.O>[CH2:7]([O:14][C:15](=[O:16])[NH:17][C:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1(CO)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Ethyl chloroformate (0.17 mL, 0.0018 mol) was added to a solution of 1-[(benzyloxy)carbonyl]aminocyclopropanecarboxylic acid (0.35 g, 0.0015 mol) and triethylamine (0.25 mL, 0.0018 mol) in THF (5.0 mL) at −10° C. The mixture was stirred at RT for 30 min., filtered, and washed with THF. Sodium tetrahydroborate (0.11 g, 0.0030 mol) in water (1.0 mL) was added to the filtrate at 0° C., and stirred at RT for 2 h. The reaction mixture was carefully quenched with 1N HCl, and extracted with EtOAc. The extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give the crude product (0.32 g, 97%). LCMS: (M+H)=222.0, (M+Na)=244.0.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=O.[C:11](OC(=O)C)(=[O:13])[CH3:12].[OH-].[K+].[CH2:20](N(CC)CC)C>>[C:11]([N:1]1[CH:2]([C:8](=[O:10])[CH3:20])[CH2:3][CH2:4][C:5]1=[O:7])(=[O:13])[CH3:12]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CC
Agent: [K+]
Agent: [OH-]
Product: CC(=O)C1CCC(=O)N1C(C)=O
Temperature: 60 °C

Procedure:
A 500-mL round bottom flask under argon atmosphere is charged with L-glutamic acid 4 (21 g, 0.143 mol), a catalytic amount of N,N-dimethylaminopyridine (150 mg, 1×10−3 mol), acetic anhydride (75 mL) and triethylamine previously distilled over KOH (75 mL). The reaction mixture is maintained at 60° C. for 16 hours. The progression of the reaction is followed by TLC (eluent: ethyl acetate/petroleum ether at a ratio of 8/2). The crude reaction product is concentrated under reduced pressure (rotary evaporator and vane pump) and then taken up in 200 mL of dichloromethane; the organic layer is then washed five times with 100 mL of deionized water and then treated over animal carbon. The product obtained after evaporation of the solvent is purified by crystallization from petroleum ether/CH2Cl2. The crystals are rinsed with petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]OS(C)(=O)=O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOCC.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:45][CH2:46]3)[CH2:13][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCN1CCC(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
A mixture of 0.55 g of the compound obtained in step C of EXAMPLE 30, 0.47 g of 4-phenylpiperidine and 0.5 g of K2CO3 in 4 ml of DMF is heated at 80° C. for 5 hours. After cooling, the reaction mixture is poured into iced water and extracted with AcOEt, the organic phase is washed with 1 N NaOH solution and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in ether, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.25 g of the expected product. M.p.=208° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Treat a solution 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (5.79 g, 20.7 mmol) in dichloromethane (50 mL) at −78° C. with oxalyl chloride (1.99 mL, 22.8 mmol), DMSO (3.5 mL, 49.5 mmol), and triethylamine (8.6 mL, 62.1 mmol). Stir at −78° C. for 30 min, warm to room temperature and stir for 1 h. Quench with ice and extract with dichloromethane (100 mL). Wash with saturated aqueous NaHCO3, saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and purify (silica gel chromatography, eluting with 40:60 to 50:50 ethyl acetate:hexanes) to give the title compound (4.53 g, 78%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:13]
Reactant: CCO
Reactant: O=C(O)CCCCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCBr
Reaction time: 12 h
Yield: 76.1 %

Procedure:
To a solution of 8-bromooctanoic acid (0.20 g, 0.89 mmol), DMAP (0.12 g, 0.99 mmol), and ethanol (0.05 g, 0.99 mmol) in methylene chloride (20 mL) was added EDCI (0.19 g, 0.99 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and evaporated to give 8-bromooctanoic acid ethyl ester (0.17 g, 75%). This bromide reacted with 4-(3-adamantan-1-yl-ureido)butyric acid 822 in the same manner as that used for the preparation of 883 to provide 879 (0.19 g, 65%) as a solid: 1H NMR (CDCl3) 1.26 (3H, t, J=6.9 Hz), 1.32-1.35 (6H, m), 1.59-1.66 (10H, m), 1.82 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J=6.9 Hz), 2.36 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05-4.14 (5H, m), 4.31 (1H, s); LC-MS (ESI) m/z calcd for C25H42N2O5 [M+H]+ 451.31, found [M+H]+ 451.20; mp 58-59 C. Anal. (C25H42N2O5) C, H, N.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17].O>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.6 mmol) of 1,2,4-triazole are added, with stirring, to a solution of 0.11 g (47 mmol) of sodium in 30 ml of n-propanol at room temperature. The mixture is heated to reflux temperature and a solution of 15.4 g (47 mmol) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours, then cooled and added to water. The mixture is extracted with methylenechloride, and the organic phase is dried over sodium sulphate and evaporated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-ylmethyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210° C.; MS: 432 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN([CH:30]=[O:31])C.Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([CH:30]=[O:31])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a suspension of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine (2 g, 7.79 mmol) in anhydrous tetrahydrofuran, cooled to −78° C. under nitrogen atmosphere, lithium bis(trimethylsilyl)amide (11.7 mL, 11.68 mmol) was added dropwise at −78° C. and the resulting reaction mixture stirred at −78° C. for 1 h. Subsequently DMF was slowly added and the mixture stirred for further 30 min. The temperature was allowed to rise to −5° C. over 10 min and then cooled again to −78° C. The resulting reaction mixture was transferred via cannula into ice-cold aqueous 1M HCl (400 mL) and stirred vigorously. The aqueous phase was extracted with ethyl acetate (2×150 mL). The organic layer was washed with water (1×125 mL), brine (2×125 mL), dried over Na2SO4 and filtered. The solvent was reduced in vacuo to afford the title compound as an orange-brown solid (1.82 g, 82%). 1H NMR (400 MHz, CDCl3): δ 10.19 (1 H, s), 4.03 (4 H, t, J=4.90 Hz), 3.87 (4 H, t, J=4.90 Hz).