Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.CS([C:26]1[S:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[N:34]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:26]2[S:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[N:34]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)c1nc2cnccc2s1
Reactant: NCC1CCN(CC2COc3ccccc3O2)CC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)OCC(CN1CCC(CNc3nc4cnccc4s3)CC1)O2
Temperature: 150 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of 6.7 parts of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinemethanamine dihydrobromide, 3.26 parts of 2-(methylsulfonyl)thiazolo[4,5-c]pyridine, 4.25 parts of sodium carbonate and 18 parts of N,N-dimethylacetamide was stirred for 2 hours at 150° C. The reaction mixture was poured into ice water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 1.15 parts (20%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]thiazolo[4,5-c]pyridin-2-amine; mp. 147.1° C. (compound 58).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O.[N:12]#[C:13]Br>CO.[Pd].O>[NH2:12][C:13]1[O:6][C:5]2[C:4](=[C:10]([OH:11])[CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: O=[N+]([O-])c1c(O)cccc1O
Reactant: N#CBr
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1nc2c(O)cccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a stirred solution of 30 g (193 mmol) 2-nitroresorcinol in 900 ml methanol was added 2.00 g 10% palladium on charcoal, and the mixture was then stirred for 18 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate, which contained 2-aminoresorcinol, added dropwise to a stirred solution of 22.5 g (213 mmol) cyanogen bromide in 230 ml methanol and 100 ml water. Stirring was continued for 2 h at room temperature, and then the mixture was concentrated in vacuo. To the residue was added aqueous sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether afforded 27.0 g (93%) 2-amino-benzooxazol-4-ol as a beige crystalline solid. EI-MS m/e (%): 150 (M+, 100), 107 (28).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:20]([CH:23]=[O:24])=[CH:21][N:22]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2.[BH4-].[Na+]>CO.O>[OH:24][CH2:23][C:20]1[N:8]2[C:9]3[C:14]([N:15]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]2=[N:22][CH:21]=1)=[CH:13][C:12]([C:16]([F:17])([F:19])[F:18])=[CH:11][CH:10]=3
Reactant: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(CO)cnc12
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of the 4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline-1-carbaldehyde prepared as in example 36 (8 mg, 0.024 mmol) in anhydrous methanol (300 μL), cooled at 0° C. was added sodium borohydride (2 mg, 0.047 mmol). The mixture was allowed to warm to room temperature over 1 h under argon and then diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica gel, dichloromethane/methanol 9/1) to afford the title compound as a white solid (5 mg, 61%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:15]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1=[O:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1COCCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1COCCN1C(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 100 ml, three neck round bottom flask is equipped with a stir bar, a condenser, an addition funnel, a thermometer, and a temperature control device (Therm-O-Watch™, I2R). To this reaction flask is added the 3-oxomorpholine synthesized above (5.5 g, 0.054 moles), triethylamine (Aldrich, 6.0 g, 0.059 moles), and toluene (Baker, 15.0 g). To the addition funnel is added benzoyl chloride (Aldrich, 7.6 g, 0.054 moles). The reaction is heated to 90° C. under argon, and the benzoyl chloride is charged dropwise into the flask. After the addition is complete, the reaction is heated under reflux for 10 hours under argon as a white precipitate forms. The reaction mixture is then cooled and the precipitate is removed by vacuum filtration. Solvent is stripped from the resulting filtrate on a Kugelrohr apparatus at 2 mmHg and 70° C. for 1 hour to obtain the desired N-benzoyl-3-oxomorpholine as an oil.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].CN(C)C=O.[NH2:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.225 g. (25 mole) of BOC-L-Met was dissolved in 160 ml. of degassed dimethylformamide and cooled under nitrogen to 0° C. 4.55 g. (25 mmole) of L-Leu-OMe was dissolved in 80 ml. of dimethylformamide and set aside. To the BOC-L-Met was added 5.38 ml. of diphenylphosphorylazide in 10% excess followed by 3.48 ml. of triethylamine in 10% excess, followed by the L-Leu-OMe. The reaction mixture was stirred at 0° C. for 3 hrs., then at room temperature for 16 hrs. The solution was concentrated and treated with 3:1 dimethylformamide/water and mixed bed resin, whereupon it crystallized out on the resin. The resin and crystals were filtered and the resin washed with dimethylformamide to isolate the product. The filtrate was then concentrated and recrystallized from ethyl acetate/hexane. 7.74 g. of product was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:27][CH:28]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:27][CH:28]1[CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of commercially available 2-(((benzyloxy)carbonyl)amino)acetic acid (6.70 g, 32.0 mmol) and EDCI (8.42 g, 43.9 mmol) was stirred in anhydrous DCM for 15 minutes and then added to a solution of commercially available tert-butyl 3-aminoazetidine-1-carboxylate (5.02 g, 29.1 mmol) and HOBt (4.45 g, 29.0 mmol, mono hydrate). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated ammonium chloride solution, 1 N NaOH solution, brine and the organic layer dried over Na2SO4. After concentration in vacuo, the residue was purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a white solid after drying under high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.6 %

Procedure:
To a stirred solution of methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 1.79 mmol) in THF (10 ml) was added 0.25 N NaOH (10 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-bromo-4-[N′-(2-chlorophenyl) ureido]phenylacetic acid (643 mg, 94%) as colorless powder. 1H-NMR (DMSO-d6) δ 3.56 (s, 2H), 7.05 (m, 1H), 7.21 (dd, J=8.6, 1.7 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 8.86 (s, 1H), 8.89 (s, 1H), 12.40 (s, 1H); MS (ESI) m/z 382 (M++1), 384(M++3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[NH2:13][OH:14].C1(C)C=CC=CC=1>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[OH:14])/[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C/C(=N/O)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 97 %

Procedure:
1-(2,4-dihydroxyphenyl)ethanone (4.5 g, 29.6 mmol) was dissolved in pyridin (17 mL). Hydroxylamine hydrochloride (2.1 g, 29.6 mmol) was added in small portions over 10 minutes. After stirring at room temperature over night the green-yellowish solution was partitioned between water and ethyl acetate. The organic phase was washed twice with water and once with 0.2 M hydrochloric acid, and was finally concentrated. The oily residue was treated with water, evaporated to yield a white semi solid residue, which was treated with toluene and evaporated to give the titled compound (4.8 g, 98%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][NH:42][CH:39]([CH3:41])[CH3:40])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1

Procedure:
3′,4′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 29 (2.5 g, 4.9 mmol) and iso-propyl amine (1.8 mL, 14.7 mmol) in dry methanol (160 mL) were reacted in a similar manner to that described under 34 to afford 38. Yield 2.4 g (87%); mp 177-179° C.; MS (FAB) 566 (M++1); IR (KBr) 3423, 1635; 1H NMR (200 MHz, CDCl3) δ 8.02 (d, J=8.5 Hz, 1H), 7.70-7.32 (m, 12H), 7.11-6.98 (m, 3H), 6.64 (s, 1H), 5.24 (s, 2H), 5.23 (s, 2H), 4.14-4.09 (m, 3H), 3.05 (s, 2H), 2.92-2.68 (m, 3H), 1.09 (d, J=6.2 Hz, 6H). Analysis Calcd for C35H35NO6: C, 74.32; H, 6.24; N, 2.48. Found: C, 74.46; H, 6.19; N, 2.36.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([Sn](CCCC)(CCCC)CCCC)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:28]=[CH:27][C:26](I)=[C:25]([CH3:30])[C:22]=1[C:23]#[N:24]>C1(C)C=CC=CC=1.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>[NH2:20][C:21]1[CH:28]=[CH:27][C:26]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:25]([CH3:30])[C:22]=1[C:23]#[N:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)s1
Reactant: Cc1c(I)ccc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(Cl)s2)ccc(N)c1C#N
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A solution of 5.9 grams (0.015 mole) of (5-chlorothien-2-yl)tributyl tin and 3.0 grams (0.015 mole) of 2-amino-5-iodo-6-methylbenzonitrile in 150 mL of toluene was stirred, and 0.2 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) was added. The reaction vessel was evacuated, and then back-filled with dry nitrogen gas. This process was repeated two more times. The reaction mixture was then heated to reflux where it was stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride, and the solution was filtered through a fiber-glass pad to remove the catalyst. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.0 grams of 2-amino-6-methyl-5-(5-chlorothien-2-yl)benzonitrile, mp 108°-110° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1>CSC.CCCCCC.[Cu](I)I>[CH2:1]([CH:8]1[CH2:9][CH2:10][CH2:11][C:6](=[O:12])[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: O=C1C=CCCC1
Agent: I[Cu]I
Solvent: CSC
Solvent: CCCCCC
Product: CCCCC1CCCC(=O)C1
Temperature: -78 °C

Procedure:
A solution of copper iodide (6.3 mmol) in dimethyl sulphide (12 ml) is cooled to 50° C. A solution of butyl lithium (6.2 mmol) is added dropwise accompanied by stirring and stirred for a further 5 to 15 mins. The reaction mixture is cooled to −78° C. and then a solution precooled to −78° C. of cyclohex-2-enone (6 mmol), dissolved in dimethyl sulphide (1 ml), is slowly added dropwise. After stirring for one hour at −78° C. the mixture is quenched with saturated aqueous ammonium chloride solution. The reaction mixture which has been heated to room temperature is extracted with diethyl ether. The combined ether phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulphate. After evaporating-off of the solvent the residue obtained is taken up in hexane, the solution is filtered and concentrated by evaporation. After chromatography of the residue on silica gel with ethyl acetate/hexane 1:4 pure 3-butylcyclohexanone is obtained (Tetrahedron 1989, 45 (2), 425-434).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:30][C:24]3([CH3:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:10]=2)[CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reactant: CC1(N)CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(Nc2ncc(C(N)=O)c(N[C@@H]3CCC[C@H](O)C3)n2)CCOCC1
Temperature: 180 °C
Yield: 10.7 %

Procedure:
4-((1R,3S)-3-Hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.740 g, 2.354 mmol; synthesis described herein), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (0.892 g, 5.88 mmol), DIEA (1.645 mL, 9.42 mmol) and NMP (20 mL) were combined and heated for 1 h at 180° C. in a microwave. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (0-10% methanol in DCM) to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)pyrimidine-5-carboxamide (88 mg, 0.252 mmol, 10.70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (br. s., 1H), 8.35 (s, 1H), 6.76 (br. s., 1H), 4.65 (d, J=4.69 Hz, 1H), 3.56 (dd, J=3.32, 6.83 Hz, 4H), 3.40-3.47 (m, 1H), 2.20-2.29 (m, 2H), 2.10 (d, J=10.93 Hz, 1H), 1.76-1.89 (m, 2H), 1.66-1.73 (m, 1H), 1.50-1.59 (m, 2H), 1.39 (s, 3H), 1.16-1.26 (m, 1H), 1.03-1.12 (m, 3H). MS (ESI) m/z 350.4 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH:24][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
1.21 g (12 mmol) of triethylamine was added to a solution of 2.33 g (10 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in 100 ml of tetrahydrofuran, 1.55 g (10 mmol) of phenylacetyl chloride was added dropwise thereto under ice-cooling, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.21 g (91%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH2:10])(=[O:9])=[O:8].[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[S:7]([NH2:10])(=[O:9])=[O:8])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccsc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1sccc1NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.3 %

Procedure:
A mixture of 3-amino-thiophene-2-sulfonic acid amide (100 mg, 0.56 mmol) and 3-bromo-benzenesulfonyl chloride (97 μL, 0.67 mmol) in anhydrous pyridine (3 mL) was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was taken up in dichloromethane (25 mL). The organic phase was washed with 1 M hydrochloric acid, saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography, using 4-6% methanol in dichloromethane as the eluent, gave 147.6 mg (66% yield) of the title compound.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([CH:24]=[O:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][CH2:15]1>O1CCCC1>[CH:1]1([CH:24]([OH:25])[C:21]2[N:19]3[CH2:20][C@H:14]([C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=4[F:6])[CH2:15][CH2:16][C@@H:17]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:18]3=[N:23][CH:22]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C3CC3)cnc21
Reaction time: 0.5 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran; 1.53 mL, 0.77 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (60 mg, 0.15 mmol) in tetrahydrofuran (1 mL) at 0° C. After 30 min, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 434.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:26])([F:25])[F:24])=[N:15][C:16]([C:17](=[O:22])N(OC)C)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([Mg]Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:25])([F:24])[F:26])=[N:15][C:16]([C:17]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CON(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: Br[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1
Yield: 32.7 %

Procedure:
1-(Methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and then cyclopentylmagnesium bromide (0.79 mL, 1.58 mmol) was added dropwise to the solution at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 50 mL of saturated ammonium chloride and 10 mL of saturated brine were added. The crude mixture was extracted with ethyl acetate (100 mL×3), and then the combined organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 28a (0.1 g, yield 30%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([CH2:18][NH2:19])O>C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Ti+4]>[CH2:4]([C:3]1[O:2][CH2:1][CH2:18][N:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCCO
Reactant: CCCCCCCCCCCC(=O)OC
Agent: [Ti+4]
Agent: CC(=O)[O-]
Product: CCCCCCCCCCCC1=NCCO1

Procedure:
Following the procedure of Example 1, lauric acid methyl ester was reacted with ethanolamine in the presence of titanium tetraacetate to form 2-undecyl-2-oxazoline. The quantities used were as follows:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[S:24][C:23]([C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][N:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][SiH3])[CH:40]=2)[C:32]3=[O:37])=[O:26])=[CH:22][CH:21]=1.[O:47]1CCCC1>>[Cl:19][C:20]1[S:24][C:23]([C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][N:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][OH:47])[CH:40]=2)[C:32]3=[O:37])=[O:26])=[CH:22][CH:21]=1
Reactant: O=C(Nc1cccc2c1CN(Cc1cccc(C[SiH3])c1)C2=O)c1ccc(Cl)s1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(Nc1cccc2c1CN(Cc1cccc(CO)c1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under argon and at room temperature, a solution of tetra-n-butylammonium fluoride (1 M in THF, 4.6 ml, 4.6 mmol) is added to a solution of 5-chloro-N-{1-oxo-2-[3-(silylmethyl)benzyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide (2.0 g, 3.8 mmol) in tetrahydrofuran (38 ml). The reaction mixture is stirred at room temperature for 14 h and concentrated under reduced pressure. The crude product is used without further purification for the next reaction.