Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)=[C:9](C)[CH:8]=2)CCCC1.[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])C.Cl[C:35]1[N:40](C)[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[N:36]=1.[C:49]([OH:56])(=[O:55])/[CH:50]=[CH:51]/[C:52]([OH:54])=[O:53]>C(OCC)(=O)C.CC(C)=O.O1CCCC1>[C:49]([OH:56])(=[O:55])/[CH:50]=[CH:51]/[C:52]([OH:54])=[O:53].[CH3:35][N:40]1[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)[N:36]=[C:19]1[N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:27][N:29]3[CH2:32][CH2:33][CH2:31][CH2:30]3)=[CH:12][CH:11]=2)[CH2:14]1
Reactant: CCN(CC)CC
Reactant: Cc1cc(N2CCCC2)ccc1C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(N2CCCC(c3ccc(CN4CCCC4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 8 h
Yield: 84.4 %

Procedure:
4N Hydrogen chloride in ethyl acetate was added to 3-(4-(1-pyrrolidinyl)-methylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.26 g, 0.75 mmol) and stirred overnight. After filtration and dryness, triethylamine (0.5 ml, 3.6 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (0.14 g, 0.63 mmol) and tetrahydrofuran were added and stirred at 70° C. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure and the residue was dissolved into ethyl acetate. A solution of fumaric acid (0.095 g, 0.82 mmol) in acetone was added and the resulting precipitate was filtered and dried to give the title compound (0.29 g, 76%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[C:8]([C:10]1[C:15]2[N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[O:18][C:14]=2[C:13]([F:22])=[C:12]([NH:23][C:24](=O)OC(C)(C)C)[C:11]=1[CH3:31])#[N:9].C=O.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[CH3:2][N:23]([CH3:24])[C:12]1[C:13]([F:22])=[C:14]2[O:18][C:17]([CH:19]3[CH2:20][CH2:21]3)=[N:16][C:15]2=[C:10]([C:8]#[N:9])[C:11]=1[CH3:31]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(NC(=O)OC(C)(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(N(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Trifluoroacetic acid (5 ml) was added to tert-butyl (4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazol-6-yl)carbamate (I-318) (70 mg, 0.211 mmol), followed by stirring at room temperature for 1 hour. The reaction liquid was evaporated under reduced pressure, and the resulting residue was dissolved in acetic acid (2 ml). 38% formaldehyde (153 μl, 2.11 mmol) was added to the solution, then sodium cyanoborohydride (70 mg, 2.11 mmol) was added, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction liquid, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, ethyl acetate:n-hexane=3:1, v/v) to obtain the entitled compound (23 mg, 42%) as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=C(O)/C=C/c1cccc(F)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(F)c1
Yield: 94.7 %

Procedure:
A mixture of trans 3-fluorocinnamic acid (32.3 g), thionyl chloride (48 g) and dry benzene (300 ml) was heated at reflux for 2 hours. Solvent and excess thionyl chloride were removed by distillation under reduced pressure leaving trans 3-fluorocinnamoyl chloride (34 g) as an oil. A solution of trans 3-fluorocinnamoy chloride (3.3 g) in dry toluene (100 ml) was added with stirring to a solution of cyclopropylamine (2.5 g) in dry ether (100 ml) at ambient temperature. The reaction mixture was heated at 30°-34° C. for 2 hours, and the solvent and excess amine were removed under reduced pressure. The residue was triturated with water, filtered and recrystallized from ethanol:water (1:10) to give trans 3-fluoro-N-cyclopropylcinnamamide (3.3 g), m. p. 90°-91° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([OH:14])=O.[CH3:20][CH:21]([NH2:23])[CH3:22]>>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH:23][CH:21]([CH3:22])[CH3:20])=[O:14]
Reactant: CC(C)N
Reactant: COc1ccc(C(=O)O)cc1OC1CCCCC1O
Product: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1O

Procedure:
Prepared as in Example 24a from (±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic acid (Example 129e) and propan-2-amine as a white solid (80%). 1H NMR (400 MHz, DMSO-d6) δ 1.14 (d, J=8.0 Hz, 6H), 1.25-1.30 (m, 4H), 1.61 (m, 2H), 1.85 (m, 2H), 3.56 (m, 1H), 3.79 (s, 3H), 4.03-4.12 (m, 2H), 4.81 (d, J=4.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.45-7.49 (m, 2H), 8.01 (d, J=8.0 Hz, 1H). MS 308 (MH+).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCO>C(N(CC)CC)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc3cc(Cl)ccc3[nH]2)CC1
Temperature: 170 °C
Yield: 40 %

Procedure:
To 2,5-dichloro-1H-benzimidazole (100 mg, Synth. Commun, 1998, 28, 9, 1703-12) and Boc-piperazine (150 mg) was added dry EtOH (5 mL) and then triethylamine (0.112 mL) and the reaction was heated in a microwave at 150° C. for 1 h. The reaction was then heated further for 2.5 h at 170° C. The solvent was then evaporated in vacuo and the residue purified by column chromatography 30-100% EtOAC:hexanes to afford the title compound (72 mg) as a colourless oil.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:63][C@@H:64]2[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]2)(=O)=O)=CC=1.O>CN1CCCC1=O.C(OCC)(=O)C>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:63][C@@H:64]5[CH2:68][O:67][C:66]([CH3:70])([CH3:69])[O:65]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H]5COC(C)(C)O5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 389 mg (0.600 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 3 ml of 1-methyl-2-pyrrolidone, 489 mg (1.50 mmol) of cesium carbonate and 344 mg (1.20 mmol) of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluene sulfonate were added, and the reaction solution was stirred at 70° C. for 2 hours. After completion of the reaction, water and ethyl acetate were poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-50/50 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 400 mg (0.524 mmol) of 4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyrimidin-2-yl)piperidin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:2]([CH3:1])[CH:7]=1)(=[O:9])[CH3:10]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)=O)cc1C
Reaction time: 66 h

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (5 g), methyl bromoacetate (3.70 ml) and anhydrous potassium carbonate (5.52 g) in acetone (100 ml) was stirred for 66 hours. The mixture was filtered and the liltrate evaporated to give an oil which crystallised on standing giving methyl 4-acetyl-2-methylphenoxyacetate, 7.2 g: m.p. 51°-53° C.; NMR (d6DMSO) δ7.79 (1H, s), 7.77 (1H, d), 6.94(1H,d), 4.93 (2H, s), 3.71 (3H, s), 2.50 (3H, s+DMSO), 2.24 (3H, s).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=O.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]#[N:5])=[O:12]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Product: N#C[C@@H]1CCCN1C(=O)CCl

Procedure:
In a similar procedure as employed in a patent (WO98/19998), L-proline amide (10.0 g) was reacted with chloroacetyl chloride (7.0 ml) and then subjected to dehydration reaction to give the title compound (7.7 g, yield (Y.:51%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:8][O:20]2)=[CH:15][CH:14]=1
Reactant: C[S+](C)C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placed under N2 then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g, 3.2 mmol) was added as a solid after 15 min, followed after a further 30 min by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone. The mixture was stirred at room temperature for 24 hours then diluted with ethyl acetate and washed with 1:2 water/brine, water and brine (×2). The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (1.01 g, 97%), which was used without further purification. LCMS (PS-A2) Rt 4.07 min [M−H]− 355.
Reaction SMILES: [CH3:1][CH:2]([NH2:17])[CH2:3][O:4][CH2:5][CH:6]([O:8][CH2:9][CH:10]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH3:11])[CH3:7].[C:18]1(=[O:24])O[C:21](=[O:22])[CH:20]=[CH:19]1.O>C1C=CC=CC=1>[C:18]1(=[O:24])[NH:16][C:21](=[O:22])[CH2:20][CH2:19]1.[CH3:1][CH:2]([NH2:17])[CH2:3][O:4][CH2:5][CH:6]([O:8][CH2:9][CH:10]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH3:11])[CH3:7]
Reactant: O=C1C=CC(=O)O1
Agent: CC(N)COCC(C)OCC(C)OCC(C)N
Solvent: c1ccccc1
Solvent: O
Product: O=C1CCC(=O)N1

Procedure:
A succinimide of a polyoxypropylenediamine of about 2000 MW(JEFFAMINE® D-2000) is prepared as follows: A mixture of JEFFAMINE® D-2000 (750g., 0.375 mole) and maleic anhydride (18.4g., 0.187 mole) was refluxed in benzene until water removal was complete (reaction temperature 145°-195° C.). The resulting product was then vacuum stripped at 180° C./3MM. The product analyzed as follows -- total amine 0.64 meq./g., primary amine 0.43 meq./g.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([N:6]1[CH2:22][CH2:21][C:9]2([CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4]>O1CCOCC1>[ClH:1].[CH3:2][S:3]([N:6]1[CH2:7][CH2:8][C:9]2([CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride in 1,4-dioxane (4.0M, 0.50 mL) was added to tert-butyl 8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (21.0 mg, 0.0000659 mol) at rt. The mixture was stirred at rt for 1 h and then the solvent was evaporated, and the residue was dried under high vacuum to afford the desired product. LCMS: m/z 255.5 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Cl:24])C(=O)C1.[OH-].[Na+]>O1CCCC1.O.C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[Cl:24]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a 500 mL flask was added methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (5 g, 19.48 mmol) [from Example 95] and NCS (3.12 g, 23.37 mmol) in tetrahydrofuran (THF) (100 ml) (50 mL). After stirring for 4 h at 70° C., the yellow reaction solution was treated with 6M NaOH (32 mL, 195 mmole) and stirred an additional 2 hours. The reaction solution was diluted with H2O (50 mL) and DCM (200 mL). The organic layer was separated and the aqueous layer made acidic with 6N HCl. The acidic aqueous solution was extracted with DCM (3×200 mL), dried over Na2SO4, and concentrated to give the crude product [2.6 g, 48%] as a tan solid: LCMS (ES) m/z 277 (M+H)+.
Reaction SMILES: [Na].[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:25]=[C:26]([OH:27])[N:10]=[C:8]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[N:9]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: N=C(N)N1CCCCC1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCCCC3)n2)CC1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Sodium (1 mol) was dissolved in anhydrous ethanol (400 mL). To the obtained solution, Piperidine-1-carboxamidine (0.5 mol) was carefully added in portions. Then 4-(2-Ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.5 mol) was added dropwise, and the mixture was stirred at reflux for 4-6 h (monitored by TLC), cooled to room temperature, concentrated, diluted with water (300 mL) and acidified with acetic acid to pH-4. The formed precipitate was collected by filtration, washed with water and dried to afford 4-(6-Hydroxy-2-piperidin-1-yl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (82 g, 45%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([I:16])=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH3:20].C(N(CC)CC)C>C(O)(C)C.O1CCOCC1>[I:16][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH3:20])[N:7]=2)=[CH:12][N:11]([CH:13]([CH3:15])[CH3:14])[N:10]=1
Reactant: COC(=O)N[C@@H](C)CN
Reactant: CC(C)n1cc(-c2ccnc(Cl)n2)c(I)n1
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2I)n1

Procedure:
A solution of Intermediate 2-chloro-4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidine (1.4 g, 4.01 mmol), (S)-methyl 1-aminopropan-2-ylcarbamate (0.8 g, 6 mmol) and triethylamine (2.8 ml, 20 mmol) in isopropanol (30 ml) and dioxane (20 mL) was heated in a sealed vessel at 125° C. for 48 hours. The cooled mixture was concentrated under vacuum, and aqueous sodium bicarbonate was added to the residue. The mixture was extracted with ethyl acetate, and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (1:2 hexanes/ethyl acetate eluant) to provide the title compound as a white solid. MS m/z 445.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]12([C:27]([Cl:29])=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:29].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:27]([C:17]34[CH2:26][CH:21]5[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]5)[CH2:24]3)[CH2:18]4)=[O:28])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NCCN1CCN(c2cccc(Cl)c2)CC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
To a stirred solution of [4-(m-chlorophenyl)piperazino]ethylamine (2.5 g, 0.01 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5 g, 0.018 mol) and triethylamine (3.6 g, 0.018 mol) were added. Stirring was continued at room temperature overnight. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue was dissolved in ethyl acetate (10 mL) and subjected to column chromatography using silica gel and ethyl acetate as the eluent. The title compound was separated and converted to the dihydrochloride salt with ethanolic HCl (0.7 g), m.p. 210°-213° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.Br[CH2:38][CH2:39][P:40](=[O:47])([O:44][CH2:45][CH3:46])[O:41][CH2:42][CH3:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:42]([O:41][P:40]([CH2:39][CH2:38][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9](=[O:23])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:4]=3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1)(=[O:47])[O:44][CH2:45][CH3:46])[CH3:43]
Reactant: CCOP(=O)(CCBr)OCC
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)OCC
Temperature: 110 °C
Yield: 72.5 %

Procedure:
A mixture of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (30 mg, 0.06 mmol, Zimmermann et al., Bioorg. Med. Chem. Lett. 1996, 6, 1221), diethyl 2-bromoethylphosphonate (30 μL, 0.12 mmol) and K2CO3 (20 mg, 0.16 mmol) in 2.5 mL of DMF was heated at 110° C. for 8 hours when most of the starting materials were consumed as judged by LCMS analysis. The solid material was filtered off. The filtrate was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica gel chromatography using 10% MeOH/CH2Cl2 to provide 28 mg (55%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.32 (t, 6H), 1.92-20.3 (m, 4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56 (s, 2H), 4.05-4.14 (m, 4H), 7.07(s, 1H), 7.18 (d, 2H, J=5 Hz), 7.30 (dd, 1H, J=6, 8 Hz), 7.33-7.45 (m, 3H), 7.84 (d, 2H, J=8 Hz), 8.01 (s, 1H), 8.51 (dd, 2H, J=4, 9 Hz), 8.58 (d, 1H, J=2 Hz), 8.70 (dd, 1H, J=2, 5 Hz), 9.25 (s, 1H); 31P (121.4 MHz, CDCl3) δ 30.5; MS (m/z) 644 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19]O)=[CH:7]2.O=S(Cl)[Cl:23]>C(Cl)(Cl)Cl>[Cl:23][CH2:19][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1]
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CCl

Procedure:
Prepared according to Procedure C using (8-methyl-2-o-tolylquinolin-3-yl)-methanol (670 mg, 2.5 mmol) and SOCl2 (0.91 mL, 5 eq) in CHCl3 (10 mL). After isolation, the resultant oil was carried on crude without purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH3:39])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S@:17](=[O:48])[C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)C[S@](=O)[C@H]12)c1csc(N)n1
Yield: 69 %

Procedure:
4-Methoxybenzyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (see example 7) (250 mg, 0.44 mmol) in ethyl acetate (25 ml) was stirred in an ice bath and a solution of m-chloroperbenzoic acid (75 mg, 0.44 mmol) in ethyl acetate (5 ml) was added. After 10 min the reaction mixture was washed with dilute aqueous sodium hydrogen carbonate then water followed by drying (magnesium sulphate) and evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with acetone/ethyl acetate mixtures to give the title compound as a white solid (179 mg, 69%); νmax (CHCl3) 1800, 1730, 1680 and 1610 cm-1 ; δH (CDCl3) 1.48-1.64 (1H,m), 1.89-2.00 (2H,m), 2.33-2.47 (1H,m), 3.29 and 3.75 (2H, ABq, J 19 Hz), 3.82 (3H,s), 3.84-3.96 (2H,m), 4.09 (3H,s), 5.06 (1H,dd, J 7, 9 Hz), 5.22 (2H,s), 5.55-5.8 (1H, br s, exch), 6.16 (1H,dd, J 4.5, 10 Hz), 6.91 (2H,d, J 7.9 Hz), 6.98 (1H,s), 7.35 (2H,d, J 9 Hz) and 7.55-7.65 (1H,br, exch). [Mass spectrum: +ve ion (thioglycerol) MH+ (590)].