Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O1CCCC1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:17]1([C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of 12.0 g. of 4-carboxybenzaldehyde, 13.6 g. of N,N'-carbonyldiimidazole and 100 ml. of tetrahydrofuran is allowed to stand for one hour, then 9.4 ml. of piperidine is added. The reaction mixture is allowed to stand for 18 hours, then heated at reflux temperature for one hour. Water is added and the solvent is distilled off. Methylene chloride is added and the solution is washed with 25 ml. of concentrated hydrochloric acid, then with water then is dried over magnesium sulfate. The mother liquor is concentrated to yield p-piperidinocarbonylbenzaldehyde as an oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]=O>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[CH3:42])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: C=O
Product: COC(=O)Cc1ccc(CN(C)c2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl) quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate and formaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 569; HRMS: calcd for C34H27F3N2O3, 568.1974; found (ESI, [M+H]+), 569.2039; Anal. Calcd for C34H27F3N2O3: C, 71.82; H, 4.79; N, 4.93. Found: C, 71.57; H, 4.64; N, 4.87.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][O:23][C:24]([NH:26][C@H:27]1[C@H:31]([CH2:32][CH3:33])[CH2:30][NH:29][CH2:28]1)=[O:25].C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][C@@H:31]([CH2:32][CH3:33])[C@H:27]([NH:26][C:24]([O:23][CH3:22])=[O:25])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC[C@@H]1CNC[C@H]1NC(=O)OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC
Yield: 56 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.36 g), trans-3-methoxycarbonylamino-4-ethyl pyrrolidine (0.94 g), diisopropylethylamine (0.88 g), and acetonitrile (20 ml) was refluxed for 15 hours. The precipitated crystals wee collected by filtration, and dried to give 5-amino-1-cyclopropyl-7-(trans-3-methoxycarbonylamino-4-ethyl-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.15 g), recrystallized from chloroform-ethanol, m.p. 231°-232° C.
Reaction SMILES: CO.CN1[C:8](=[O:9])CCC1.[H-].[Na+].Br[C:13]1[N:18]=[C:17]2[N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20]([OH:22])=[N:21][C:16]2=[N:15][CH:14]=1>CCOC(C)=O>[CH3:8][O:9][C:13]1[N:18]=[C:17]2[N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20]([OH:22])=[N:21][C:16]2=[N:15][CH:14]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 200 °C
Yield: 29 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with MeOH (2.0 equiv) and NMP (20 volume equivalents). To the resulting solution was added NaH (2.0 equiv), resulting in gas evolution. (S)-6-Bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv) was then added to the reaction, and the resulting mixture was immediately fitted with a septum and cap and heated to 200° C. in a microwave for 30 min. The reaction was then diluted with EtOAc, washed twice with saturated aq. NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (29%) as a white solid. LCMS m/z (APCI)=271.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][C:14]=1[O:24][CH3:25].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])=[O:22])=[CH:15][C:14]=1[O:24][CH3:25]
Reactant: COc1cc(CCC(=O)O)ccc1O
Reactant: CC(C)CCCCCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COc1cc(CCC(=O)OCCCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 76.5 %

Procedure:
8-Methyl-1-nonanol (752 mg, 4.74 mmol), 3-(4-hydroxy-3-methoxyphenyl)propionic acid (977 mg, 4.98 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). Toluene (5 ml) and anhydrous magnesium sulfate (1 g) were added, and the mixture was stirred with heating in an oil bath at 50° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, toluene (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Toluene (50 ml) was added, and the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml×3) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (chloroform:n-hexane:ethyl acetate=1:1:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 8-methylnonyl 3-(4-hydroxy-3-methoxyphenyl)propionate (1.22 g, yield 76.2%) as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].[C:31]([OH:36])(=[O:35])[CH:32]([CH3:34])[OH:33].C1(C)C=CC=CC=1>O>[CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:29])[CH3:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].[C:31]([O-:36])(=[O:35])[CH:32]([CH3:34])[OH:33]
Reactant: CC(O)C(=O)O
Agent: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)C(=O)[O-]
Reaction time: 11.5 h

Procedure:
200 g β-sitosterol, 250 g lactic acid, and 500 ml toluene were dissolved in a 5 l flask. The mixture was refluxed at 110-115° C. at the same time as water (free water+reaction water) was collected using water separation apparatus, in order to monitor the progress of the reaction. Reaction time was 11.5 h. At this point, 68 ml of water had been collected (free water: 33.8 ml+reaction water 34.2 ml), representing a 77.5% conversion in relation to the starting material. The toluene was evaporated from the reaction mixture using a rotavapor, and the product was dried in a vacuum oven at 40-60° C. The esterification experiment was repeated 5 times.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(OC)(O[CH3:19])(=O)=O>>[CH3:19][O:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C(=NO)c1csc(C)n1
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Yield: 84.5 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.3 g.) and dimethyl sulfate (0.18 g.) were reacted according to a similar manner to that of Preparation (8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH2:6]=[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[CH3:8].ClC(Cl)C.ICI>[Cl-].[NH4+]>[CH3:6][C:7]1([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)[CH2:1][CH2:8]1
Reactant: CC[Zn]CC
Reactant: C=C(C)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: ICI
Product: COC(=O)c1ccc2cc(C3(C)CC3)ccc2c1
Temperature: 25 °C
Yield: 151.5 %

Procedure:
Diethylzinc (1.0 M in Hexane)(6.30 ml, 6.30 mmol) was added to a solution of methyl 6-(prop-1-en-2-yl)-2-naphthoate (0.57 g, 2.5 mmol).in dichloroethane at 0° C. Diiodomethane (1.01 ml, 12.6 mmol) was then added dropwise to the mixture solution and the resultant mixture was stirred at 60° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride (30 mL), and the mixture was extracted with CH2Cl2 (30 ml×3). The combined organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), and the organic layer was dried over Na2SO4. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate-hexane (1:20) to give 0.91 g of the title compound as white solid. 1H NMR (270 MHz, CDCl3) ppm 0.75-0.95 (2H, m), 0.95-1.13 (2H, m), 1.52 (3H, s), 3.97 (3H, s), 7.41 (1H, d, J=9.9 Hz), 7.74 (1H, s), 7.82 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=8.6 Hz), 8.04 (1H, d, J=8.6 Hz), 8.56 (1H, s). MS (ESI) m/z: not observed M+ peak.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)=O)=CC=1.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:26]2.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH3:19][CH2:18][O:17][C:15]([CH2:14][O:13][CH2:12][CH2:11][N:26]1[C:27]2[C:23](=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[C:25]1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:16]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: CCOC(=O)COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCn1c(C(=O)OCC)cc2c(C)cccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 45.4 %

Procedure:
A solution of ethyl [2-(toluene-4-sulfonyl-oxy)ethoxy]acetate (3.90 g, 12.9 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a mixture of ethyl 4-methyl-1H-indole-2-carboxylate (2.50 g, 12.3 mmol), 60% sodium hydride (0.50 g, 12.5 mmol) and N,N-dimethylformamide (45 ml) at room temperature, and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into a 10% aqueous sodium chloride solution and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate: n-hexane=2:98) to obtain 1.86 g of ethyl 1-[(2-ethoxycarbonylmethoxy)ethyl]-4-methyl-1H-indole-2-carboxylate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1.CO.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:12][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Cc1cc(Br)c2nccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2ccccc2)c2nccnc2c1

Procedure:
A mixture of 400 mg of 5-bromo-7-methyl-quinoxaline, 244 mg of phenylboric acid and 100 mg of tetrakis(triphenylphosphine)palladium in 12 ml dioxane, 4 ml of methanol and 3.6 ml 1 M aqueous sodium carbonate solution is refluxed for three hours under an argon atmosphere. Then the reaction mixture is evaporated down and the residue is distributed between ethyl acetate and water. The ethyl acetate phase is separated off, dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (85:15 to 70:30) as eluant.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C(OCC)C.O1CCCC1>[F:31][C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Brc1cccc2cc3ccccc3cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1cccc2cc3ccccc3cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.2 millimoles n-butyl lithium were dropped into a solution of 1 millimole bromoanthracene in 5 milliliters diethyl ether at 5° C. The solution was cooled to 0° C, was stirred for 1 hour, and then was cooled further to -78° C.; 1.2 millimoles N-fluorobenzenesulfonimide prepared according to Example 1 above in 5 milliliters tetrahydrofuran were dropped into the mixture which was stirred for 1 hour. The temperature was allowed to rise to 20° C. while stirring was continued. The reaction mixture was quenched by pouring into saturated ammonium chloride solution and extracted with diethyl ether. Fluoroanthracene was obtained in 76% yield.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.C(OCC)C>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])=[O:5]
Reactant: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)Nc2cccc(C(=O)CBr)c2)no1
Reaction time: 0.5 h

Procedure:
A solution of bromine (12.5 g) in chloroform (60 ml) was added to a slurry of 3'-acetyl-5-methyl-3-isoxazolecarboxanilide. 1/4 hydrate (19 g) in chloroform (190 ml). The mixture was stirred for 1/2 hour and diluted with diethyl ether. The product was filtered and dried. Yield 21.0 g = (84%,) m.p. 172°-174°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C@@H:16]2[CH2:22][C:21]([F:24])([F:23])[CH2:20][CH2:19][NH:18][C:17]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:15]([C@@H:16]2[CH2:22][C:21]([F:24])([F:23])[CH2:20][CH2:19][NH:18][C:17]2=[O:25])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:27])=[O:28])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCC(F)(F)C[C@H]1N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 91.8 %

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.105 g, 0.2 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1) and stirred overnight. After extraction with aqueous sodium bicarbonate solution the organic layer was dried (MgSO4) and evaporated to yield 80 mg (94%) of 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-piperidin-4-ylmethyl-benzenesulfonamide;
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)o1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2cn(CCCCCl)c(=O)[nH]c2=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
5-(2,4-Dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep61, 300 mg, 1.45 mmol) was dissolved in dry DMF (4 ml) and K2CO3 (300 mg, 2.17 mmol) was added. The mixture was stirred at room temperature for 1 h, then a solution of 1-bromo-4-chloro-butane (commercially available from Aldrich, 496 mg, 2.9 mmol) in dry DMF (1 ml) was added. After stirring the reaction at room temperature for 48 hours, water was added and the mixture was extracted with diethylether. The aqueous layer was then extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was used without further purification in the next step (200 mg, 47% yield).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:13](OC)OC)[CH3:12]>>[CH3:10][N:11](/[CH:13]=[N:9]/[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: NC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzamide (1-135) in DMF-DMA was stirred for 3 h at 110° C., then cooled to rt. The solid was collected by filtration, the filter cake washed with PE and air dried to give the desired (E)-N-((dimethylamino)methylene)benzamide (compound II-135).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[CH2:12][CH2:13][N:14]=[C:15]=[O:16].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:15]1[O:16][CH2:12][CH2:13][N:14]=1
Reactant: O=C=NCCCl
Reactant: Cc1cccc(CN)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(CNC2=NCCO2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 1.0 gram (0.0074 mole) of 2,3-dimethylbenzylamine and 0.69 gram (0.0081 mole) of 2-chloroethylisocyanate in 10 mL of 1,4-dioxane was heated to reflux where it stirred for about 18 hours. The reaction mixture was allowed to cool and an aqueous solution of sodium hydroxide (4.0 mL of a 3.0 molar solution) was added. The reaction mixture was heated to reflux for about 18 hours then allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure to leave a viscous oil residue. The residue was suspended in 50 mL of ethyl acetate and washed with 20 mL of water. The organic phase was extracted with 20 mL of 3.0 molar aqueous hydrochloric acid. The aqueous extract was made basic by adding 3.0 molar aqueous sodium hydroxide and the basic mixture was extracted with 50 mL of ethyl acetate. The extract was dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield 0.81 gram of the title compound as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[C:17](Cl)(=O)C>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([O:9][CH3:17])=[O:8])([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.1 %

Procedure:
To an ice cooled stirred solution of 3-nitro-5-(trifluoromethyl)benzoic acid (25.00 g, 106.3 mmol) in methanol (500 mL) was added acetyl chloride (22.00 g, 280.2 mmol) dropwise over 20 min. After the addition was complete, the reaction mixture was stirred for 20 min at 0° C., then heated at reflux for 6 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, filtered through a silica gel and concentrated under reduced pressure to provide methyl 3-nitro-5-(trifluoromethyl)benzoate (24.65 g, 93%) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:35])[CH2:31][CH2:32][O:33][CH3:34]>>[CH3:34][O:33][CH2:32][CH2:31][C:30]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:29]=1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 242 mg (1.640 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 350 mg (46% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:27])=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[OH:29][CH:3]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:27])=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:28])[CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: Cc1cc(CCC(=O)c2sc(C)c(CC(C)C)c2C)cc(C)c1OCC(O)CN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c(CC(C)C)c2C)cc(C)c1OCC(O)CNS(C)(=O)=O
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of rac-3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-propan-1-one (545 mg, 1.31 mmol) in DCM (27 mL), DIPEA (270 mg, 2.09 mmol) is added. The mixture is cooled to 0° C. before methanesulfonylchloride (180 mg, 1.51 mmol) is added. Stirring is continued at 0° C. for 1 h. The mixute is diluted with DCM, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of MeOH to give N-(2-hydroxy-3-{4-[3-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl)-methanesulfonamide (545 mg) as a yellow oil; LC-MS: tR=1.06 min, [M+1]=496.24.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13][C:14]1[N:15]([CH2:21][C:22](O)=[O:23])[C:16]([Br:20])=[C:17]([Br:19])[N:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>O>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:22](=[O:23])[CH2:21][N:15]2[C:16]([Br:20])=[C:17]([Br:19])[N:18]=[C:14]2[Br:13])[CH2:3][CH2:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)Cn1c(Br)nc(Br)c1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1c(Br)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 mL 2-piperazin-1-yl-pyrimidine was added to a mixture of 17 g (2,4,5-tribromo-imidazol-1-yl)-acetic acid, 16.6 g TBTU, 7.3 mL TEA and 100 mL DMF. The reaction mixture was stirred for 2 h at RT and subsequently added to water. The precipitate was filtered to give 23 g desired product. Rt: 0.93 (method B), ESI+: 507