Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]=2[NH:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:10]1[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]1=2)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1c[nH]c2c(=O)ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2ccccc(=O)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester (1 g, described in example 2), potassium carbonate (1 g) and ethyl bromoacetate (1 g) in dimethylformamide (DMF, 50 ml) was stirred at 25° C. for 5 hr. The reaction mixture was diluted with water and extracted with chloroform. The chloroform extract was evaporated to dryness. The residue was purified by chromatography on silica gel using chloroform-methanol (99:1) as the eluant. The appropriate fractions were pooled and crystallized from acetone to give the title compound; mp 152°-154° C.; nmr (CDCl3) δ1.3 (t, 6H), 4.3 (m, 4H), 4.85 (s, 2H), 7.0 (m, 3H), 8.2 (m, 2H); ir (CHCl3) 1740, 1730, 1690, 1630 cm-1 ; uv λ max (MeOH) 349 nm (ε12,625), 235 (18,760), 212 (25,070); Anal Calcd for C17H17NO6 : C, 61.63% H, 5.17% N, 4.23% Found: C, 61.67% H, 5.23% N, 4.25%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1)#[N:2].C(N(CC)CC)C.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34]>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[C:7]2[CH:24]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(N2CCN(c3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4yl)-N'-phenylethylene-diamine (0.36 g, 1.12 mmole, from Example 21, part A) and triethylamine (0.12 g, 1.18 mmole) in methylene chloride (4 ml) cooled to 0° C. was added a solution of 4-nitrophenyl chloroformate (0.24 g, 1.18 mmole) dissolved in methylene chloride (3 ml). The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 5% aqueous HCl solution. The organic phase was washed with 2N NaOH solution, saturated NaCl solution, dried over MgSO4 and solvent evaporated to obtain 420 mg of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (4:1) to obtain 0.30 g of the title compound as a pure white solid. m.p.=166°-168° C. 1H NMR (DMSO-d6) δ7.61 (m, 4H), 7.35 (m,2H), 7.03 (m, 1H), 6.95 (d, J=8.21 Hz, 1H), 5.21 (dd, J=6.45 and 11.73 Hz, 1H), 3.88 (m, 2H), 3.36 (m 1H), 3.14 (m, 1H), 2.03 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H); 13C NMR (DMSO-d6) δ158.08, 157.13, 140.58, 132.86, 131.56, 128.63, 121.86, 121.63, 119.15, 118.52, 117.05, 102.54, 77.31, 44.68, 42.06, 36.56, 34.06, 29.36, 24.01; MS: (M+H)+ @348.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C@@H:11]([O:13][CH2:14][C@H:15]([O:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=3)[N:34]=[CH:35][C:28]=12)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1)=[O:17])[CH3:12])(C(C)(C)C)(C)C>C1COCC1.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C@@H:15]([O:26][C:27]2[N:32]=[CH:31][N:30]=[C:29]3[N:33]([C:36]4[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][N:37]=4)[N:34]=[CH:35][C:28]=23)[CH2:14][O:13][C@@H:11]([CH3:12])[CH2:10][OH:9])=[N:20][CH:21]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
HCl (4M in Dioxane) (0.606 mL, 2.42 mmol) was added to (2S)-3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AO4) (300 mg, 0.48 mmol) in THF (5 mL) and water (0.5 mL) at room temperature. The resulting solution was stirred at room temperature for 10 minutes. The reaction mixture was evaporated and the residue partitioned between EtOAc (25 mL) and sat NaHCO3 (10 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak AS column, eluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent. The fractions containing the desired compound were evaporated to dryness to afford the product (173 mg, 70.7%). 1H NMR (400 MHz, CDCl3) δ 1.17 (d, 3H), 2.64 (s, 1H), 3.51-3.67 (m, 2H), 3.69-3.79 (m, 1H), 4.11-4.28 (m, 2H), 6.05 (t, 1H), 7.45-7.50 (m, 1H), 7.66-7.71 (m, 1H), 7.99-8.04 (m, 1H), 8.18-8.25 (m, 2H), 8.47 (s, 1H), 8.60-8.65 (m, 2H), 9.10 (s, 1H) m/z (ESI+) (M+H)+=504.40; HPLC tR=1.96 min
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:46])[CH2:36][CH2:37]5)=[O:34])=[C:28]([F:47])[CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:60][CH2:59]2)[CH2:57]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)c(F)c4)ccn3)CC2)C1
Reaction time: 120 h
Yield: 25.2 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (181 mg) and triethylamine (0.259 ml) at room temperature, followed by stirring for 5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (24.0 mg, 25%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[C:9]([CH3:13])=[N:8][C:5]2=[N:6][CH:7]=1.[Br:14]C1C=CC(Br)=CN=1>>[Br:14][C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[C:9]([CH3:13])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1=Nc2ncc(Cl)cc2C1(C)C
Reactant: Brc1ccc(Br)nc1
Product: CC1=Nc2ncc(Br)cc2C1(C)C

Procedure:
Compound 3 was prepared analogously to compound 1 (Example 1), except that 2,5-dibromopyridine was used as a starting material.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:21]([NH:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCc2cc(Cl)c(N)cc2C(c2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1Cl)CCN(C)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.4 g of 8-amino-7-chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 50 ml of methylene chloride was treated with 4 ml of acetic anhydride followed by addition of 10 mg. of 4-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 2 hours, and the solvent was removed in vacuo. The residue was stirred with a mixture of ether and sodium bicarbonate solution for 1 hour. The ether layer was separated, dried over sodium sulfate and evaporated in vacuo. The resulting crude product of this example (3.1 g) was used in the following step B.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc2[nH]cnc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1ncn2Cc1ccccc1

Procedure:
To a flask were added 1.0 g 4-methyl-1H-benzimidazole, 1.6 g potassium carbonate, 25 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 1.4 g Benzyl chloride were added and the mixture was heated to 60 C for 16 hours. Another 0.4 g of benzyl chloride were added and the reaction was heated to 70 C for 24 hours. The reaction was cooled to 50 C and quenched with 50 ml water and extracted with ethyl acetate. After washing with water, the solvent was removed and the product was purified by column chromatography using a gradient from 40% ethyl acetate in hexane to 75% ethyl acetate in hexane. Following removal of the solvent, the partially crystallized product was dissolved in 20 ml acetonitrile and treated with 0.1 g activated carbon. After refluxing for 20 minutes, the mixture was filtered through celite and the solvent was removed leaving a yellow oil which crystallized on standing, 1.0 g.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24][CH:25]1[CH2:30][CH:29]2[CH2:31][CH2:32][CH:26]1[CH2:27][NH:28]2>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([N:28]2[CH2:27][CH:26]3[CH2:32][CH2:31][CH:29]2[CH2:30][CH:25]3[OH:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CC2CCC1CN2
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC2CCC1CC2O

Procedure:
Following the procedures set out in Example 1, 1 part of 3,3,3-triphenylpropionyl chloride and 2 parts of 5-hydroxy-2-azabicyclo[2.2.2]octane are reacted to provide 2-(3,3,3-triphenylpropionyl)-5-hydroxy-2-azabicyclo[2.2.2]octane. 0.23 Parts of this material is reacted with 0.05 parts of lithium aluminum hydride in 3.0 parts by volume of ethyl ether to provide 2-(3,3,3-triphenylpropyl)-5-hydroxy-2-azabicyclo[2. 2. 2]octane. This compound, isolated as the hydrochloride salt, has the following structural formula. ##STR42## Administration of this material inhibits diarrhea in animals in need of antidiarrheal treatment.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][C:18]=2[O:26][CH3:27])=[C:11]([CH3:28])[N:10]=1>CN1C(=O)CCC1.CCOC(C)=O>[NH2:8][C:9]1[N:14]=[C:13]([NH:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4])[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][C:18]=2[O:26][CH3:27])=[C:11]([CH3:28])[N:10]=1
Reactant: COc1cc(CC#N)ccc1Cc1c(C)nc(N)nc1Cl
Reactant: CCC[C@H](N)CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Temperature: 140 °C
Reaction time: 50 h

Procedure:
(S)-2-Aminopentan-1-ol (0.136 g) was added to a solution of the product from step (iii) in NMP (2 mL). The resulting mixture was stirred at 140° C. for 50 h then diluted with EtOAc and washed with saturated NaHCO3 solution and saturated brine. The organic phase was dried, filtered and evaporated. The crude product was purified by column chromatography, elution gradient 5 to 10% MeOH in DCM to give the subtitle compound, 0.095 g.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]([OH:10])[CH3:9]>C(Cl)(Cl)Cl>[CH3:7][C@:8]1([C:3]2[CH:2]=[CH:1][C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:4]=2)[CH2:9][O:10]1
Reactant: CCCCCC
Reactant: CC(C)O
Solvent: ClC(Cl)Cl
Product: C[C@]1(c2ccc3ccccc3c2)CO1
Yield: 85 %

Procedure:
White solid, 85% yield, >99% ee (CHIRALCEL OJ-H, hexane/iPrOH 99.5:0.5); [α]D23 +3.3° (c=1.00, CHCl3); 1H NMR (CDCl3): δ7.85-7.80 (m, 4H), 7.51-7.43 (m, 3H), 3.06-3.04 (d, J=5.6 Hz, 1H), 2.90-2.88 ppm (d, J=5.6 Hz, 1H), 1.82 ppm (s, 3H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[O:10][CH2:11][CH2:12][OH:13].C>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccccc1OCCO
Solvent: ClCCl
Product: COc1ccccc1OCCOS(N)(=O)=O

Procedure:
The title compound was prepared by the procedure of Example 28 from sulfamoyl chloride and 2-(2-methoxyphenoxy)ethanol. The solid obtained was dissolved in 150 ml of methylene chloride, and the solution was treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from methylene chloride-petroleum ether (bp range 30°-60° C.) to give the title compound in 25% yield as white solid, mp 102°-104° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12]>ClCCl>[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CCC(=O)Cl
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Propionyl chloride (13.0 ml) was added to a suspension of aluminum chloride (20.0 g) in dichloromethane (200 ml) at 0° C. After the mixture was stirred at 0° C. for 1 hour, isobutylbenzene (23.6 ml) was added to the mixture. The mixture was stirred at 0° C. for 2 hours and poured into ice water. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residual oil was distilled under reduced pressure to give 4'-isobutylpropiophenone as a colourless oil (24.4 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][C:12](=[O:14])[CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2](=[O:1])[CH2:3][CH2:4]2
Reactant: CN
Reactant: O=C(O)Cc1ccc2c(c1)CCC2=O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc2c(c1)CCC2=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
N-Methyl(1-oxoindan-5-yl)acetamide can be obtained in the following way: 16 g of N,N'-carbonyldiimidazole are added portionwise to a solution of 12.5 g of (1-oxoindan-5-yl)acetic acid in 250 ml of tetrahydrofuran maintained at 0C. After reacting for 1 hour at a temperature in the region of 20° C., the solution is cooled to -10° C. and a stream of monomethylamine is passed into the mixture for 5 minutes. After returning to a temperature in the region of 20° C., the reaction mixture is evaporated under reduced pressure. The residue is taken up in 1 liter of dichloromethane. The organic phase is washed three times with 500 ml of distilled water, dried over magnesium sulphate and then evaporated. The resulting brown solid is purified by flash chromatography on silica (eluent dichloromethane/methanol (96/4 by volume)). 9 g of N-methyl(1-oxoindan-5-yl)acetamide are thus obtained in the form of a white solid melting at 169° C. (1H NMR spectrum in CDCl3, T=300 K δ in ppm: 2.69 (2H1 m, COH2), 2.80 (3H, d, NCH3), 3.14 (2H, t, J=5 Hz, CH2), 3.65 (2H, 5, H2), 5.47 (1H, broad s, NH), 7.26 (1H, d, J=7 Hz, arom. CH), 7.42 (1H, s, arom. CH), 7.74 (1H, d, J=7 Hz, arom. CH)).
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:12][C:11](=C)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=[O:15].[K+].[K+]>C(Cl)Cl.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([NH:8][CH:9]1[CH2:12][C:11](=[O:15])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(=O)C1
Yield: 177.6 %

Procedure:
To a vigorously stirring solution of N-Boc-3-methylene-cyclobutanamine (9.8 g, 53.5 mmol) in DCM (160 mL) and H2O (160 mL) was added K2CO3 (3 g, 21.7 mmol), followed by NaIO4 (35 g, 163.5 mmol), tetrabutylammonium chloride (0.2 g, 0.72 mmol) and RuCl3 (0.6 g, 7.6 mmol). During the course of the reaction, the organic solution turned dark brown, the catalyst turned black, while the upper aqueous layer turned white. The reaction was monitored by TLC, and upon completion, the reaction mixture was filtered through a pad of celite. The filtrates were transferred to a separatory funnel, and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with 5% NaHCO3 (2×30 mL), brine (30 mL), dried over Na2SO4, filtered and evaporated to dryness to yield a crude, which was purified by flash chromatography (silica gel/hexanes:ethyl acetate 0-60%) to yield the desired N-Boc-3-amino-cyclobutanone (7.13 g, 38.53 mmol, 72% yield): NMR (250 MHz, CDCl3) δ 4.88 (bs, 1 H), 4.13-4.29 (m, 1 H), 3.23-3.41 (m, 2 H), 2.9-3.05 (m, 2 H), 1.39 (s, 9 H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: C=CC(=O)O
Reactant: c1nnn[nH]1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCn1cnnn1

Procedure:
4.5 g of tetrazole are stirred for 8 hours at 90° with 4.5 ml of acrylic acid and 15 drops of pyridine. After cooling, 150 ml of water are added to the reaction mixture and the whole is acidified with HCl (concentrated) and concentrated under reduced pressure in a rotary evaporator. The crystalline residue is digested three times with methyl ethyl ketone and the combined organic phases are dried over sodium sulphate. After concentration by evaporation, the crystalline residue is stirred with isopropanol/ether and filtered off.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][C:33]([C:34](=[O:36])[NH2:35])=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:39][O:40][CH2:41][S:42]([C:45]1[CH:46]=[C:47]([OH:52])[C:48](=[CH:50][CH:51]=1)[OH:49])(=[O:44])=[O:43]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][CH2:41][S:42]([C:45]2[CH:51]=[CH:50][C:48]([OH:49])=[C:47]([OH:52])[CH:46]=2)(=[O:43])=[O:44])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][C:33]([C:34](=[O:36])[NH2:35])=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2ncc(C(N)=O)c2n1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2ncc(C(N)=O)c2n1

Procedure:
(6R,7R)-7-(2-Amino-4-thiazolglyoxylamido)-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was reacted with 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol according to the procedure described in Example 7. After purification of the crude product using the chromatographic procedure described in Example 7 and lyophilization of the product fractions, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-5-methylpyrazolo [1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([C:25]3([NH:29]S(C(C)(C)C)=O)[CH2:28][O:27][CH2:26]3)[CH:22]=[CH:23][CH:24]=2)=[N:4]1)=[CH2:2].Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[CH:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([C:25]3([NH2:29])[CH2:28][O:27][CH2:26]3)[CH:22]=[CH:23][CH:24]=2)=[N:4]1)=[CH2:2]
Reactant: C=Cn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: C=Cn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of N-{3-[3-(1-ethenyl-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}tert-butylsulfinamide (1.63 g, 3.22 mmol) in 40 mL of methanol was cooled in an ice bath. 4M HCl in dioxane (3.2 mL, 13 mmol) was added and the mixture was stirred for 45 min. Saturated aqueous NaHCO3 solution was added and mixture was warmed to ambient temperature and extracted with EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 3-(3-{1-ethenyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-amine as an oil. Calcd (M+1)+: 402.4. Found: 402.8
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:14]([O:1][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1cccs1
Product: O=C(Oc1cc[nH]c(=O)c1)c1cccs1
Yield: 74.8 %

Procedure:
The general procedure of Example 18 was followed using 2.00 g of 4-hydroxy-2-pyridone and 3.17 g of 2-thenoyl chloride, thereby producing 2.98 g of the title compound in a yield of 75%.