Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](Cl)(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N[CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].C[N:30](C)C=O.Cl>O>[Cl:1][C:2]1[C:10]([S:11](=[O:13])(=[O:12])[NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:20](=[O:21])[CH3:19])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Reactant: CN(C)C=O
Reactant: NCC(=O)Nc1ccccc1
Agent: Cl
Solvent: O
Product: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The mixture of 38.8 g 4-chloro-5-chlorosulfonyl-3-nitrobenzoic acid, 39.9 g of 2-aminoacetanilide and 150 ml of dimethylformamide is stirred for 21/2 hours at room temperature. It is poured into 1.7 lt of water and 20 ml of concentrated hydrochloric acid while stirring, the precipitate formed is filtered off and washed with water. It is dissolved in 600 ml of hot ethanol, 900 ml of hot water are added, the mixture filtered and the filtrate left in the cold, to yield the 4-chloro-5-(2-acetamidophenylsulfamoyl)-3-nitrobenzoic acid melting at 225°-227° with decomposition. [In the analogous manner the 5-(4-acetamidophenylsulfamoyl)-isomer is prepared, m.p. 245°-246° (dec.).]
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([I:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([I:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(I)cc(I)cc1I
Product: O=C(Cl)c1c(I)cc(I)cc1I
Temperature: 25 °C

Procedure:
2,4,6-Triiodobenzoic acid (15 g) was suspended in thionyl chloride (75 ml) was refluxed. Thirty minutes after the starting material was dissolved, the reaction solution was cooled and evaporated in vacuo. The residue was dissolved in hot benzene (40 ml), cooled to room temperature, filtered and the filtrate evaporated in vacuo. Yield: 13.6 g. I.R. (KBr): 1785 cm -1 (--COCl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])[S:5][C:6]=1[Cl:7].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)OC1>O1CCOCC1.O.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>[Cl:7][C:6]1[S:5][C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])=[CH:3][C:2]=1[C:45]1[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1C(F)(F)F)NC(=O)c1cc(Br)c(Cl)s1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 12 h
Yield: 25.9 %

Procedure:
To a solution of 1,1-dimethylethyl {(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (750 mg, 1.38 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (762 mg, 5.52 mmol), tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h where additional tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol) were added. After 12 h, the solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (194 mg, 26%) as a white solid: LC-MS (ES) m/z=544.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[CH:4][N:3]=1.ClC1N=CC(OC2CCN(C)CC2)=CN=1.[F:30][C:31]1([F:77])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([O:47]CC4C=CC(OC)=CC=4)[CH2:44][C:43]([CH3:58])([CH3:57])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1>>[F:77][C:31]1([F:30])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([OH:47])[CH2:44][C:43]([CH3:57])([CH3:58])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][N:62]([C:2]4[N:7]=[CH:6][C:5]([O:8][C@@H:9]5[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]5)=[CH:4][N:3]=4)[CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:74])([F:75])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1
Reactant: CN1CC[C@@H](Oc2cnc(Cl)nc2)C1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CN1CCC(Oc2cnc(Cl)nc2)CC1
Product: CN1CC[C@@H](Oc2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)C1

Procedure:
Reactions similar to those of Reference Example 29 and Example 38 were performed except for using 2-chloro-5-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyrimidine, which was prepared by a method similar to that of Reference Example 30, instead of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine, and from 100 mg (0.155 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 58 mg of the title compound was obtained as a white solid (yield: 44%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[I-:21].[Na+]>CC(C)=O>[F:15][C:14]([F:17])([F:16])[C:13]([N:10]1[CH2:9][CH2:8][C:7]2[CH:19]=[CH:20][C:4]([CH2:3][CH2:2][I:21])=[CH:5][C:6]=2[CH2:12][CH2:11]1)=[O:18]
Reactant: [I-]
Reactant: O=C(N1CCc2ccc(CCCl)cc2CC1)C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(N1CCc2ccc(CCI)cc2CC1)C(F)(F)F

Procedure:
To 800 mg (2.62 mmol) 1-[7-(2-chloro-ethyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone (preparation 6a) in 40 mL acetone is added 471 mg (3.14 mmol) sodium iodide. The reaction mixture is refluxed overnight, excess sodium iodide is added and the reaction mixture is refluxed additional three days. The solvent is evaporated, the residue is diluted with EtOAc and washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond; C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:14]([O:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[CH:13]=[CH2:12]
Reactant: CC(O)C(=O)c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(C)C(=O)c1ccccc1
Yield: 93.3 %

Procedure:
A mixture of 225 grams of 2-hydroxypropiophenone, 247 grams of allyl bromide, 415 grams of potassium carbonate and 5 grams of potassium iodide is heated to reflux for twenty four hours in 1 liter of acetone. After cooled, insoluble matters are removed by filtration, the filtrate is concentrated, the residue is dissolved in benzene, and the solution is washed with 10% sodium hydroxide solution. After washing with water, the solution is dried with anhydrous magnesium sulfate and benzene is evaporated therefrom. The resulting oil is distilled in vacuo to give 266 grams of 2-allyloxypropiophenone, colorless oil, b.p. 120° to 124° C.
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:20]([CH3:22])[CH3:21])=[N:17][CH:18]=1>C1(C)C=CC=CC=1>[CH3:21][C:20]1([CH3:4])[CH2:22][CH:19]1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][O:10][CH3:9])=[CH:18][N:17]=1
Reactant: COCOc1ccc(C=C(C)C)nc1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: ICI
Product: COCOc1ccc(C2CC2(C)C)nc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Diiodomethane (24.8 ml, 308 mmol) was added dropwise to a solution of diethylzinc (200 ml, 220 mmol) 1.1 M in toluene at 0° C. After the addition, the solution was stirred at RT for 40 minutes and then recooled to 0° C. when 5-(methoxymethoxy)-2-(2-methylprop-1-enyl)pyridine (21.3 g, 110 mmol) in toluene (150 mL) was added dropwise through an addition funnel. The reaction was allowed to come to RT and was stirred 12 hrs before being quenched at 0° C. by the addition of a 10:1 saturated ammonium chloride/ammonium hydroxide aqueous solution. The layers were separated and the aqueous layer was diluted with water and extracted into ethyl acetate. The combined organic layers were washed with 10:1 saturated ammonium chloride/ammonium hydroxide aqueous solution, water, brine, dried over sodium sulfate, and concentrated. The crude product was purified through a plug of silica (10:1 Hexanes/EtOAc) to afford the titled compound. MS m/z: 208.2 (100%, M+1).
Reaction SMILES: [C:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[C:16]([OH:24])=[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:1]2
Reactant: CCCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Yield: 73.6 %

Procedure:
A solution of 1-[2-(1-heptyn-1-yl)-4-(methyloxy)phenyl]-2-phenylethanone (112) (0.57 g, 1.78 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.42 g (74%) of compound 113 as a light brown viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=6.9 Hz, 3H), 1.10-1.25 (m, 4H), 1.35-1.50 (m, 2H), 2.47 (t, J=7.9 Hz, 2H), 3.93 (s, 3H), 5.16 (s, 1H), 7.06-7.12 (m, 2H), 7.23 (s, 1H), 7.32-7.38 (m, 2H), 7.43-7.49 (m, 1H), 7.50-7.56 (m, 2H), 8.08 (d, J=10.0 Hz, 1H). LCMS (ESI): m/z 321 (M+H)+, m/z 319 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[Li+].[OH-].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2cncc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCc2cncc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
Compound 27b (1.22 mmol, 340 mg) was combined with LiOH (4.9 mmol, 118 mg) in 3 mL of THF, 3 mL of MeOH, and 3 mL of water. The mixture was stirred at room temperature for 4 h and was then combined with 15% aqueous citric acid and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2SO4, and concentrated under vacuum to give 288 mg of 27c.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([CH2:50]C(Cl)=O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:50]([C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:5])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH2:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccccc2N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 2-Amino-benzenethiol (2.41 g, 19.23 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. (0.990 g, 21%)
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:4])[NH:6][CH:7]=2)=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)N2CCOCC2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 1 (1 equivalent) in DMF, at ambient temperature, was added morpholine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 4 was used without purification. FIA/MS (M+1) 333.3, (M−1) 331.2; 1H NMR was consistent with expected structure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15](=[O:31])/[C:16](/[C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:17]\[O:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH3:21])[C:12](=[O:32])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].C([BH3-])#N.[Na+].[CH:37](=O)[CH3:38]>C([O-])(=O)C.[Na+].O>[NH2:30][C:27]1[S:28][CH:29]=[C:25](/[C:16](=[N:17]/[O:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH3:21])/[C:15]([NH:14][CH:13]2[C:12](=[O:32])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][NH:1][CH2:37][CH3:38])[CH2:4][S:5][C@H:6]23)=[O:31])[N:26]=1
Reactant: CCC(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reactant: CC=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCNCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(CC)C(=O)O)c3csc(N)n3)[C@H]2SC1

Procedure:
The cephalosporin starting material may be prepared as follows: To a stirred solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]ceph-3-em-4-carboxylic acid (more polar isomer, 2.6 g) in 2.5% (w/v) pH 5.5 sodium acetate buffer (50 ml) was added sodium cyanoborohydride (0.34 g), followed by acetaldehyde (0.3 ml) in water (5 ml) over 40 minutes. The reaction mixture was then concentrated, diluted to 50 ml with water, and the pH adjusted to 3.5 with HOAc. Careful chromatography on Diaion HP20SS, eluting with H2O/CH3CN, (92.5:7.5) gave 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxypropoxyimino)acetamido]-3-ethylaminomethylceph-3-em-4-carboxylic acid, having the following n.m.r. spectrum in solvent A: 0.96 (t, 3H); 1.18 (t, 3H); 1.81 (quintet, 2H); 2.94 (q, 2H); 3.38 (d, 1H); 3.42 (d, 1H); 3.61 (d, 1H); 3.78 (d, 1H); 4.46 (t, 1H); 5.03 (d, 1H); 5.76 (d, 1H); 6.88 (s, 1H). Retention time 4.2 minutes on a reversed phase Partisil PXS 10/25 ODS-2 column, using MeOH/H2O/HOAc, 30:70:1, v/v/v, as eluant.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][C@H:3]1[CH2:9][OH:10].C(Cl)(=O)C(Cl)=O.[CH3:18][C@@H:19]([CH2:23][CH3:24])[C:20](O)=[O:21]>>[CH3:18][C@@H:19]([CH2:23][CH3:24])[C:20]([O:10][CH2:9][C@@H:3]1[CH2:4][C:5](=[C:6]([CH3:7])[CH3:8])[C:2]1([CH3:11])[CH3:1])=[O:21]
Reactant: CC[C@H](C)C(=O)O
Reactant: CC(C)=C1C[C@@H](CO)C1(C)C
Agent: O=C(Cl)C(=O)Cl
Product: CC[C@H](C)C(=O)OC[C@@H]1CC(=C(C)C)C1(C)C

Procedure:
A method for making [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate (2), said method comprising (or consisting essentially of or consisting of) reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) or reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl lithium, and then methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3); reacting (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) with phosphorus oxychloride to form (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4); reacting (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4) with p-toluenesulfonic acid to form (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5); reacting (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5) with lithium aluminum hydride to form [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol [(R)-maconelliol] (6), and reacting [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol (6) with oxalyl chloride and (S)-2-methylbutanoic acid to form [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]1[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH2:8]1.COC(C)(C)C.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]21[CH2:7][CH2:8]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCCCC12CC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=C1CCCCCCC12CC2
Yield: 75.9 %

Procedure:
64.3 g (180 mmol) of methyltriphenylphosphonium bromide was added while stirring under nitrogen to a solution of 19.1 g (170 mmol) of potassium tert-butylate in 350 ml of dry tetrahydrofuran and the mixture was heated to reflux. Then, a solution of 22.8 g (150 mmol) of spiro[2.7]decan-4-one in 50 ml of dry tetrahydrofuran was added dropwise to the boiling reaction mixture. The mixture was heated under reflux for a further 2 hours. After cooling, the reaction mixture was poured into 11 of tert-butyl methyl ether/water (1:1). The organic phase was separated and the aqueous phase was extracted twice with 500 ml of tert-butyl methyl ether. The organic extracts were combined, dried over sodium sulfate and concentrated on a rotary evaporator. After flash chromatography (n-pentane, Rf=0.97) on silica gel, there was obtained 17.1 g (76%) of 4-methylenespiro[2.7]decane (V, n=2) as a colorless liquid with the following properties:
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][Mg]Br>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: COc1cccc(C[Mg]Br)c1
Product: COC(=O)c1cc2c([nH]1)C(Cc1cccc(OC)c1)CC2

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-methoxybenzylmagnesium bromide (0.25 M in hexanes, 25 mL, 6.3 mmol) according to General Procedure 3 to give the exo olefin-containing compound (E)-methyl 6-(3-methoxybenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation (with 5% Pd/C) according to General Procedure 6, and was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 40% EtOAc. The material was carried to the next step without further characterization.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:3](=[O:2])[C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:23])[F:22])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 27 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using cyclopropylamine instead of cyclopropanemethylamine, to the title compound (20 mg, 27%) which was obtained as a white solid. MS: m/e=439.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].I[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][C:14]3([CH2:20][CH2:21][N:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][CH2:13]3)[C:18]2=[O:19])=[CH:24][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: CC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-(4-iodo-phenyl)-ethanone. White solid. MS (ESI): 447.1 MH+).