Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]([NH2:37])=[NH:36]>C1COCC1>[NH2:36][C:35]([NH2:37])=[N:34][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: N=C(N)N
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Oc1ccc(=O)[nH]n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1ccc(=O)[nH]n1
Reaction time: 2 h

Procedure:
A solution of 540 mg of 3-methylsulfonyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)benzoic acid [obtainable by reacting 3-methylsulfonyl-4-chlorobenzoic acid with 3-trimethylsilyl-oxy-6-oxo-1,6-dihydropyridazine] and 300 mg of carbonyldiimidazole in 15 ml of THF is stirred at room temperature for 2 hours, and 383 mg of guanidine are then added to it. This mixture is then stirred for a further two hours. After the customary working-up, N-diaminomethylene-3-methylsulfonyl-4-(1,6-dihydro-6-oxo-3-pyridazinyloxy)benzamide is obtained, m.p. 268-270°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([CH:21]1[CH2:31][C:24]2[S:25][C:26]([C:28]([OH:30])=[O:29])=[CH:27][C:23]=2[CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20].BrCC1C=CSC=1.C(C(O)=O)CCCCCC.C([N-]C(C)C)(C)C.[Li+].[CH2:57]([C:64]1[CH:69]=[CH:68][C:67](O)=[CH:66][CH:65]=1)[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:16]([CH:21]1[CH2:31][C:24]2[S:25][C:26]([C:28]([O:30][C:67]3[CH:66]=[CH:65][C:64]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[CH:69][CH:68]=3)=[O:29])=[CH:27][C:23]=2[CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC1Cc2cc(C(=O)O)sc2C1
Reactant: CCCCCCCc1ccc(O)cc1
Agent: BrCc1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)[N-]C(C)C
Solvent: ClCCl
Solvent: CCCCCCCC(=O)O
Product: CCCCCCCc1ccc(OC(=O)c2cc3c(s2)CC(CCCCC)C3)cc1

Procedure:
1.63 g of dicyclohexylcarbodiimide in 2.5 ml of methylene chloride are added to a mixture of 1.78 g of 5-n-pentyl-5,6-dihydro-4-H-cyclopenta[b]thiophene-2-carboxylic acid (which can be prepared from 3-bromomethylthiophene by reaction with n-heptanecarboxylic acid and lithium diisopropylamide, subsequent cyclization via the corresponding acid chloride, reduction of the carbonyl group (for example Wolff-Kishner reduction), Friedel-Crafts acetylation and a haloform reaction), 0.098 g of 4-dimethylaminopyridine, 1.42 g of 4-n-heptylphenol and 12 ml of methylene chloride at 10°, with stirring. After the mixture has been stirred at room temperature for 15 hours, it is filtered with suction over silica gel and the solvent is evaporated off. Recrystallization from ethanol gives 4-n-heptylphenyl 5-n-pentyl-5,6-dihydro-4-H-cyclopenta[b]thiophene-2-carboxylate of m.p. 64° and c.p. 82°.
Reaction SMILES: N[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[BrH:16].N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:16][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(C(F)(F)F)cc1Br
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 5-amino-2-chloro-4-nitrobenzotrifluoride (synthesized according to the method described in J. Org. Chem., 60, 18, 1995, 5838-5842, 24.9 g) and 48% aqueous hydrogen bromide (400 ml) was ice-cooled. Sodium nitrite (12.9 g) was dissolved in a small amount of water and added dropwise thereto. The reaction mixture was stirred for 4 hr while warming from −5° C. to 15° C., ice-cooled and alkalified with a 6N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration and washed with water to give a brown solid. The solid was purified by silica gel column chromatography (elution solvent:ethyl acetate-hexane (1:50)) to give 5-bromo-2-chloro-4-nitrobenzotrifluoride (17.7 g, yield 56%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][CH:4]2[CH2:3]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[F:20][C:17]([F:18])([F:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([N:7]2[CH2:8][C@@H:4]3[CH2:3][C:2](=[O:1])[CH2:22][N:5]3[C:6]2=[O:21])=[CH:10][CH:11]=1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CC2C[C@H](O)CN12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H]2CN(c3ccc(OCC(F)(F)F)cc3)C(=O)N2C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 50.3 %

Procedure:
To the solution of (S)-6-Hydroxy-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (1 g, 3.16 mmol) in dry DCM (20 mL) was added PDC (3.6 g, 9.48 mmol) portion wise under cooling. The reaction mixture was stirred at room temperature for 13 h. Then reaction mixture was filtered and washed with methanol, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (elution with 30% ethyl acetate in hexane) to yield 500 mg (50%) of the title compound as white solid. LC-MS: 315.4 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.N1C=CC(C(=O)CC(OCC)=O)=CC=1.Cl.[NH:30]=[C:31]1[CH:37]([N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]1>>[O:11]=[C:9]1[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([N:38]3[C:46](=[O:47])[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]3=[O:48])[C:31]2=[N:30][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:8]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: N=C1NCCCCC1N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1C1CCCCn2c1nc(-c1ccncn1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1), the compound was obtained as a white powder.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Pyridine (40 mL, 492 mmol) was added in a single portion to a chilled solution (0° C.) solution of indole (48 g, 410 mmol) in diethyl ether (820 mL). Ethyl chlorooxoacetate (50 mL, 451 mmol) was added dropwise. The resulting suspension was allowed to warm to ambient temperature over a period of 20 hours. The solid was isolated by filtration and washed with diethyl ether. The solid was combined with water (1 L), stirred for 1 hour, and then isolated by filtration to provide 75 g of ethyl (1H-indol-3-yl)(oxo)acetate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH: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:22]([CH3:29])([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:29])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CC(C)(N)CO
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)CC(C)(CO)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-2,4-dimethylpentan-1-ol (CAN 13893-55-5) as starting materials. MS (EI): m/e=398.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:34])([F:33])[F:32])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:27]=[N:28][NH:29][CH:30]=4)=[CH:18][CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.I[CH2:36][C:37]([F:40])([F:39])[F:38].O>CN(C=O)C>[Cl:10][C:8]1[CH:7]=[C:6]([C:11]2([C:31]([F:32])([F:34])[F:33])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:30]=[N:29][N:28]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:27]=4)=[CH:18][CH:17]=3)[CH2:12]2)[CH:5]=[C:4]([Cl:3])[CH:9]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-c3cn[nH]c3)c3ccccc23)=NO1
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Cn1cc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (2 mg) is added to a solution of 5-(3,5-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-naphthalen-1-yl]-5-trifluoromethyl-4,5-dihydro-isoxazole (3 mg, Example 2) in DMF (0.4 ml) at 0° C. After 1 hour at room temperature 2-iodo-1,1,1,-trifluoroethane (16 mg) is added and the reaction mixture is further stirred for 16 hours at room temperature. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(3,5-dichloro-phenyl)-3-{4-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-naphthalen-1-yl}-5-trifluoromethyl-4,5-dihydro-isoxazole (compound 1.18, Table 1) as a colorless wax.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 45.9 %

Procedure:
A solution of the compound of Example 52, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of CH2Cl2 was treated with triethylamine (1.10 mL, 8.00 mmol). With vigorous stirring, the solution was treated dropwise with methanesulfonyl chloride (0.217 mL, 2.80 mmol). After 18 h, the reaction was treated with 50 mL of water and the layers were separated. The aqueous portion was extracted with CHCl3 (3×30 mL). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 463 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}methanesulfonamide as a white solid.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:30]C)=[C:27]([CH3:29])[CH:28]=5)[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl>O1CCOCC1>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:32])[CH:20]=[C:21]([C:23]5[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2c[nH]c(=O)c(C)c2)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.075 g, 0.165 mmol) in 1,4-dioxane (2 mL) was added aqueous 4 M HCl (447 μL, 1.79 mmol) drop-wise. The reaction was stirred at 90° C. for 1.5 hours. The reaction was allowed to cool down to room temperature and then quenched with Et3N. The solvent was evaporated under reduced pressure. The crude compound was dissolved in ethyl acetate and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (33 mg, 46%); ESI-MS m/z calc. 439.41. found 440.5 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[C:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])=[N:24][O:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:18][CH:19]=2)[CH:8]=1)C>O.C(O)C>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[N:16]=[CH:15][C:14]([O:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:38])=[O:5])=[CH:19][CH:18]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[O:25][N:24]=1
Reactant: CCOC(=O)c1cccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(Oc2cccc(C(=O)O)c2)cn1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
NaOH (0.228 g, 5.7 mmol) in water (0.25 ml) was added to a solution of 3-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid ethyl ester (0.157 g, 0.3 mmol) in ethanol (5 ml) and the reaction mixture was stirred at room temperature for 50 h. The solvent was removed under reduced pressure and the residue diluted with water (1.5 ml) and acidified to pH 6. The resulting solution was extracted with ethyl acetate and the extract was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 3-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid as colorless oil. Yield 0.14 g (33%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1.[NH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:20]2[C:10]([S:9][CH2:8][C:5]3[N:6]=[CH:7][C:2]([N:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)=[CH:3][CH:4]=3)=[C:11]([Cl:28])[CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(N4CCCCC4)cn3)c2CC1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
In a sealed tube, add tris(dibenzylideneacetone)dipalladium(0) (3.44 mg, 0.00376 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.98 mg, 0.00752 mmol) to a mixture of 6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (242 mg, 0.501 mmol), sodium tert-butoxide (96 mg, 1.0 mmol), 18-crown-6 (13 mg, 0.050 mmol) and piperidine (496 μL, 5.01 mmol) in toluene (3 mL). Flush the mixture with nitrogen and heat overnight. Cool to ambient temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (179 mg, 73%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][S:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>C(Cl)Cl>[C:52]([O:45][C@H:30]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:29][S:28][CH2:27][C@@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCOC[C@@H](O)CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution (R)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-3-(dodecyloxy)-2-hydroxypropyl)thio)propanoate (1 eq) in DCM (0.1 M) was cooled in an ice bath. Pyridine (3.0 eq) was added followed by dodecanoyl chloride (3.0 eq). The reaction mixture was stirred for 10 minutes then warmed up to room temperature, and stirred for 2 hours. The reaction mixture was diluted with DCM, and washed with saturated aqueous NH4Cl. The aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hex to give the title product as a white solid.
Reaction SMILES: [C:1]1(S(O)(=O)=O)C=CC=CC=1.[C:11]([OH:42])(=[O:41])[CH2:12][CH2:13][C@H:14]([NH:18][C:19]([C:21]1[CH:40]=[CH:39][C:24]([NH:25][CH2:26][C@@H:27]2[NH:38][C:37]3[C:35](=[O:36])[NH:34][C:32]([NH2:33])=[N:31][C:30]=3[NH:29][CH2:28]2)=[CH:23][CH:22]=1)=[O:20])[C:15]([OH:17])=[O:16].[OH-].[Na+].C=O.S(=O)(=O)(O)O>O>[CH2:1]1[N:25]([C:24]2[CH:23]=[CH:22][C:21]([C:19](=[O:20])[NH:18][C@H:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][C:11]([OH:42])=[O:41])=[CH:40][CH:39]=2)[CH2:26][C@@H:27]2[N:38]1[C:37]1[C:35](=[O:36])[NH:34][C:32]([NH2:33])=[N:31][C:30]=1[NH:29][CH2:28]2
Reactant: Nc1nc2c(c(=O)[nH]1)N[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Reactant: O=S(=O)(O)c1ccccc1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(c(=O)[nH]1)N1CN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)C[C@H]1CN2

Procedure:
100 g of pure (6S)-tetrahydrofolic acid benzenesulfonate prepared, for example, by the method described in Swiss Patent Application No. 108, filed January 16, 1991, are suspended in water. The pH is brought to 7.5 by addition of I N sodium hydroxide solution. 15 ml of 37% strength aqueous formaldehyde solution are then added, and the mixture is adjusted to pH 2.5 with 2 N sulfuric acid. The 5,10-methylene-(6R)-tetrahydrofolic acid formed precipitates and is filtered off.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH:14]([OH:16])[CH3:15]>>[CH3:11][O:12][CH2:13][CH:14]([O:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:15]
Reactant: COCC(C)O
Reactant: O=[N+]([O-])c1cccnc1F
Product: COCC(C)Oc1ncccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example XI.1 using 2-fluoro-3-nitropyridine (142 mg) and 1-methoxypropan-2-ol (108 mg).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24]O)[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:61].N1C=CC=CC=1.O>C(Cl)Cl>[C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][Cl:61])[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Temperature: -20 °C
Yield: 112.4 %

Procedure:
To a solution of benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate (100 g) in methylene chloride (600 ml) was added at a time phosphorus pentachloride (25.6 g) at -30° C., followed by adding dropwise pyridine (9.8 g) at the same temperature. After the reaction mixture was stirred at -20° C. for an hour, it was poured into a mixture of methylene chloride (500 ml) and water (300 ml). The separated organic layer was washed with an aqueous sodium chloride, dried over magnesium sulfate and then evaporated to dryness to obtain benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-chloromethyl-3-cephem-4-carboxylate (114.5 g), mp 90°-110° C. (dec.).