Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N:19]([Si](C)(C)C)=[N+:20]=[N-:21]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:15]([N:16]2[C:17](=[O:18])[NH:21][N:20]=[N:19]2)=[CH:14][C:5]2[N:6]([CH2:11][CH2:12][CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCN1C(=O)COc2cc(F)c(N=C=O)cc21
Solvent: Cc1ccccc1
Product: CCCN1C(=O)COc2cc(F)c(-n3nn[nH]c3=O)cc21
Temperature: 25 °C
Yield: 43.7 %

Procedure:
Under a dry nitrogen atmosphere, 4.3 grams of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6yl isocyanate and 4.3 g (0.037 mole) of azidotrimethylsilane were heated at reflux for approximately 18 hours. The mixture was allowed to cool to room temperature and was diluted with toluene. This mixture was poured into ice-water forming a precipitate. The precipitate was collected by vaccum filtration, and the filter cake was rinsed first with water followed by diethyl ether. The filter cake was dissolved in acetone, and the organic solution was dried over anhydrous magnesium sulfate. This mixture was filtered, and the filtrate was evaporated under reduced pressure to yield 2.2 grams of 1-(7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6-yl)-1,4-dihydro-5H-tetrazol-5 one as a solid m.p. 145°-148° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([OH:8])=O)[CH3:2].[NH2:17][CH:18]1[C:39](=[O:40])[N:20]2[C:21]([C:36]([OH:38])=[O:37])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][C:33]([OH:35])=[O:34])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12>>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:16])[S:12][CH:13]=1)[C:6]([NH:17][CH:18]1[C:39](=[O:40])[N:20]2[C:21]([C:36]([OH:38])=[O:37])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][C:33]([OH:35])=[O:34])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:8])[CH3:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: CCON=C(C(=O)O)c1csc(NC=O)n1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Yield: 54.4 %

Procedure:
2-Ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (3.0 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.12 g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b) and 6(b) to give 7-[2-ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].[K].CN(C)C=O.[CH2:21]([N:23]([CH2:26][CH2:27]Cl)[CH2:24][CH3:25])[CH3:22]>O>[CH2:21]([N:23]([CH2:26][CH2:27][O:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1NC(C)=O
Temperature: 60 °C

Procedure:
117 g (0.5 mol) of 2-acetylamino-4-nitrophenol, in the form of the potassium salt, are introduced into 350 ml of dimethylformamide and the mixture is then heated to 60° C., whilst stirring. 88.2 g (0.65 mol) of diethylaminoethyl chloride are then added; the reaction medium is heated at 95° C. for 150 minutes and is then poured into 1,500 ml of iced water; the expected product precipitates. This product is filtered off and washed with a 0.5 N sodium carbonate solution and then with water. After filtration, the product is finally dried in vacuo at 45° C. It melts at 117° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1cc(Br)cn(-c2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Br)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Methyl 5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (0.554 g, 1.80 mmol) was dissolved in dioxane (10.5 mL) then diluted with water (3.5 mL). 2N aqueous sodium hydroxide solution (0.944 ml, 1.89 mmol) was slowly added to the mixture. The reaction mixture was stirred at room temperature overnight, then concentrated under vacuum to remove the dioxane followed by dilution with water. This aqueous layer was acidified with 1N aqueous hydrochloric acid (1.89 mL, 1.89 mmol). A precipitate formed was collected on a glass frit, and washed with minimal water. The solid was dissolved in dichloromethane and then dried over sodium sulfate. This mixture was filtered, and the filtrate was concentrated under vacuum. The remaining residue was dried under high vacuum to afford 5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid as a yellow solid (0.458 g, 1.56 mmol, 86.6% yield). MS (ESI pos. ion) m/z: 295 (MH+). Calc'd exact mass for C12H8BrNO3: 294.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NC(CO)CO
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC(CO)CO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with 2-amino-1,3-propanediol (34.1 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (50 mg, 69% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:28]I>CN(C=O)C.[Ag]=O>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[N:5]([C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH3:28]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COCCC1(C(=O)N(C)[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (2.73 mmol, 1.03 g) and silver oxide (10.9 mmol, 2.53 g) in DMF (25 mL) was added methyl iodide (160 mmol, 10 mL) at room temperature. The suspesion was stirred for 2 days at room temperature at which time TLC analysis of the mixture indicated the presence of starting material. An additional 10 mL (160 mmol) of methyl iodide and 2 g (8.6 mmol) of silver oxide were added, respectively. The suspension was stirred for 24 h and the solid was filtered through a pad of celite and was washed with ethyl acetate (30 mL) and methanol (30 mL). The filtrate was concentrated and the residue was extracted with ethyl acetate (3×30 mL).The organic layer was washed with water (20 mL) and brine solution (20 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude compound which was purified by silica gel column chromatography to obtain 530 mg (50%) as a light brown oil. HR MS (C20H28N2O6): Obs. mass, 392.1940. Calcd. mass, 392.1947 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8]1.Cl.C([O:24]N=O)CC(C)C>C(O)C>[OH:24][C:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=C1CC(CCCCCO)Oc2ccccc21
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Product: O=c1c(O)c(CCCCCO)oc2ccccc12
Reaction time: 1 h

Procedure:
2,3-dihydro-2-(5-hydroxypentyl)-4H-1-benzopyran-4-one (0.23 g) is dissolved in ethanol 95% (5 ml), and the solution is refluxed under stirring. HCl (6.2 ml) and isoamylnitrite (1.2 ml) are then added drop by drop. Stirring and heating are then stopped and the reaction mixture is allowed to stand for ca. 1 hour. The solvent is evaporated, water is then added and the product extracted with diethyl ether. The ethereal phase is dried by addition of anhydrous Na2SO4. After filtration and evaporation of the solvent an oil is obtained which is purified by chromatography with silica gel column and the mixture diethyl ether:methanol 98:2 as the eluent. 3-hydroxy-2-(5-hydroxypentyl)-4H-1-benzopyran-4-one (99.2 mg) is obtained. By crystallisation in cycloesane or diethyl ether the product in crystalline form is obtained (m.p.=111-112° C.).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: O=C1[C@@H]2C[C@@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 19B (75 g, 0.34 mol, 1 equivalent) in 2-ethoxyethanol (1.2 L), benzylamine (44 mL, 0.41 mol, 1.2 equivalents) was added. Triethylamine (60 mL, 0.43 mol, 1.28 equivalents) was then added, and the resultant mixture was refluxed for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure. This crude material was purified by column chromatography on silica gel using a gradient of 0-10% methanol-ethyl acetate to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.93-2.03 (m, 1H), 2.1-2.17 (m, 1H), 3.23 (d, 1H, J=12.3 Hz), 3.55 (d, 1H, J=4.2 Hz), 3.63 (d, 1H, J=16.5 Hz), 4.15 (m, 1H), 4.32 (bs, 1H), 4.47-4.59 (m, 3H), 5.16 (s, 1H), 7.24-7.37 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[F:20][C:21]([F:25])([F:24])[S:22]Cl.FC(F)(F)S(O)(=O)=O.ClCCCl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:22][C:21]([F:25])([F:24])[F:20])=[CH:11][C:12]=2[S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: FC(F)(F)SCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=S(=O)(c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 70 °C
Yield: 72 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (2.47 g, 0.0080 mol), trifluoromethylsulfenyl chloride (2.18 g, 0.016 mol), trifluoromethanesulfonic acid (0.12 g, 0.0008 mol) and 1,2-dichloroethane (15 mL) is placed in a pressure tube, heated at 70° C. for five days, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an amber syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as an off-white solid (2.36 g, mp 118°-122° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)O)c1C(=O)O
Reaction time: 13 h
Yield: 84 %

Procedure:
A mixture of 10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) was charged to a 2.5 L Parr hydrogenator, under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacuo to a constant weight, affording 54 g (84% yield) of 3-aminophthalic acid as a yellow product. 1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). 13C-NMR (DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 5-bromo-3-pyridineacetic acid (500 mg, 2.314 mmol) in DMF (3 mL) is added TBTU (1.11 g, 3.472 mmol). Morpholine (0.61 mL, 6.94 mmol) is added dropwise and the mixture is stirred at room temperature for 18 h. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-4.5% MeOH in DCM as the gradient to afford 2-(5-bromo-pyridin-3-yl)-1-morpholin-4-yl-ethanone.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:14][C:13]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[OH:11])[O:18][CH2:19][CH:20]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])[CH3:21])=[O:25]
Reactant: COC(=O)Cc1cc(OCC(C)=O)ccc1O
Reactant: NCC(O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(OCC(C)NCC(O)c2ccccc2)ccc1O
Yield: 3.7 %

Procedure:
Following a procedure similar to that described in Example 6, but using 0.72 g of 2-amino-1-phenylethanol, 1.5 g of methyl 2-hydroxy-5-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 21), 60 ml of benzene, 50 ml of absolute methanol and 1.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, 0.07 g of the title compound was obtained having an Rf=0.40 (thin layer chromatography over silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[CH2:26][CH2:25][CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)CCC2)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 5-aminoindan (Aldrich) according to the method described in Example 1c. Melting Point: 150-152° C. (diethylether)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A solution of 4-fluoro acetophenone (5.0 g, 3.6 mmol) and N-methyl piperazine (20 ml, 4 vol %) was heated in a sealed tube at 120° C. for 16 h. The reaction mixture was cooled to room temperature and poured into ice water. The precipitated solid was filtered and dried in vacuo to afford 7.50 g (94.5%) of 1-(4-(4-methylpiperazin-1-yl)phenyl)ethanone as solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=2[C:13]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:10])=[O:9].[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH:15]([O:22][CH3:23])[C:14]=2[C:13]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(OC)=CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(OC)CCC2

Procedure:
A mixture of Example 458B (352 mg, 0.9 mmol) and 10% Pd/C (99.8 mg) in ethyl acetate (18 mL) was hydrogenated under 50 psi of hydrogen for 2.5 days. After filtration and concentration, the desired product was isolated in quantitative yield. MS (DCI/NH3) m/e 411 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.7-7.61 (m, 2H), 7.43 (m, 1H), 7.31 (t, 1H), 7.12 (d, 1H), 7.01 (d, 1H), 4.42 (t, 1H), 3.63 (s, 3H), 3.15 (s, 3H), 2.70-2.61 (m, 2H), 1.86 (m, 1H), 1.77-1.55 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:23]([CH3:26])([OH:25])[CH3:24]>>[CH:28]1([CH2:27][C@H:22]([NH:21][C:12]([C:10]2[CH:9]=[N:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:23]([OH:25])([CH3:26])[CH3:24])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(O)[C@@H](N)CC1CC1
Product: CC(C)(O)[C@H](CC1CC1)NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol (60.21 mg, 0.42 mmol) as starting materials, and isolated (50 mg, 34.72%) as white solid, LC-MS (UV peak area, ESI) 96.42%, 410.8 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].O>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:9]=[CH:8][C:7]=1[NH:21][C:22](=[O:30])[C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:25])[F:26])(=[O:3])[CH3:2]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1N)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: 25 °C

Procedure:
Acetyl chloride (0.018 ml) was added to an ice-cooled solution of N-[2-amino-4-(phenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 184) (0.097 g) in pyridine (1 ml) and the solution was allowed to warm up to ambient temperature over 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-40% ethyl acetate/hexane to give the title compound (0.89 g) as a solid. Mp 205-207° C., NMR: 1.5 (s, 3H), 2.1 (s, 3H), 7.57-7.75 (m, 4H), 7.8-7.9 (m, 2H) 7.9-8.05 (m, 3H), 9.8 (brs, 1H), 10.1 (brs, 1H); MS (ESP−): 429.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:28]1CCOC[CH2:29]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:12](=[O:13])[N:14]([CH3:15])[CH2:16][O:28][CH2:29]2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: CC(C)c1ccc(NC(=O)N(C)C)cc1Cl
Reactant: C1COCCO1
Agent: *CO*
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)c1ccc(N2COCN(C)C2=O)cc1Cl

Procedure:
N-(3-Chloro-4-isopropyl-phenyl)-N',N'-dimethylurea (22.65 g.=0.1 mol) is dissolved in a solvent mixture comprising dioxane (50 cc.) and benzene (80 cc.). After adding p-toluenesulphonic acid (1 g.) and polyoxymethylene (8.1 g.), the solution is heated under reflux for 1 hour in a flask equipped with a Dean and Stark apparatus with a reflux condenser. 3.7 cc. of aqueous phase are collected.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:13]([O-])([O-:15])=[O:14].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: Cc1[nH]cnc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1[nH]cnc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared by nitrogenation of 5-methyl-4-phenyl-imidazole (melting point: 185-188° C.) in concentrated sulphuric acid with ammonium nitrate analogously to Example D.
Reaction SMILES: B.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH3:23][C:24]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][CH2:32][C:33]([C:35]1[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34])([CH3:26])[CH3:25].CO>O1CCCC1>[CH3:26][C:24]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][CH2:32][CH:33]([OH:34])[C:35]1[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=1)([CH3:23])[CH3:25]
Reactant: COc1ncccc1C(=O)CCCNC(=O)OC(C)(C)C
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncccc1C(O)CCCNC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 14 h

Procedure:
Borane (0.7 ml, 1M in tetrahydrofuran) was added to a solution of (3aR)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (0.05 ml, 1M in toluene) in tetrahydrofuran (2 ml) at 0° C. A solution of the product from step (a) above (0.304 g) in tetrahydrofuran (3 ml) was added over 20 minutes and then stirred at 0° C. for 4hand at 20° C. for 14 h. Methanol was added and the solution was evaporated and the residue azeotroped with methanol. Purification by chromatography on silica eluting with petrol-ether gave the sub-title compound as a colourless oil (0.255 g).