Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[CH:20]=[CH:19]4)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH:39]=[C:38]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1.CN(C=O)C>[CH2:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:35]4[CH2:36][CH:37]=[C:38]([C:41]5[C:49]6[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=6)[NH:43][CH:42]=5)[CH2:39][CH2:40]4)[O:28][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C

Procedure:
To a solution of (2R)-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.60 g, 1.5 mmole) and potassium carbonate (0.65 g, 4.70 mmole) in 30 mL of 1:1 THF/DMF was added 0.90 g (4.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The mixture was heated at reflux under nitrogen for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness under vacuum and the residue column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum and the residue recrystallized from ethanol to give 0.42 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 190° C.).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 69.8 %

Procedure:
A solution of 2.16 g of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.78 g (70%) of (R)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>ClCCl.CCCCCCC.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([Cl:9])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC#N
Product: Clc1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-bromo-2-chlorophenol (2.07 g, 10 mmol), phenyl boronic acid (3.66 g, 30 mmol), copper(II) acetate (2.0 g, 1.1 mmol) and 4A powdered molecular sieves (20 g) in dichloromethane (100 mL) was treated with triethylamine (5.0 g, 50 mmol) then stirred at ambient temperature for 5 days. The mixture was diluted with heptane (100 mL), then filtered through a bed of celite. The filtrate was concentrated under reduced pressure to remove dichloromethane. The mixture was extracted with IN hydrochloric acid, 15 wt % aqueous sodium hydroxide, brine and then dried over magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to provide (1.27 g, 45%): 1H NMR (DMSO-d6, 400 MHz) δ 7.87(s, 1H), 7.55(d, 1H), 7.40(t, 2H), 7.17(t, 1H), 6.99(m, 3H); MS MH+283; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 m/min) tr 14.42min.
Reaction SMILES: [OH-].[K+].CO.C[O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)=[O:8]>C(O)(=O)C>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[S:18]3)=[CH:11][CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Yield: 81 %

Procedure:
To a mixture of 15 ml of an aqueous solution of 20% potassium hydroxide and 50 ml of methanol was added 2.2 g of 2-(p-methoxycarbonylphenyl)imidazo[2,1-b]benzothiazole and the mixture was refluxed for 30 minutes. After the reaction was over, 4 ml of acetic acid was added to the reaction mixture and the crystals which had formed were recovered by filtration, washed successively with water, methanol and then ethanol, and dried to provide 1.7 g of 2-(p-carboxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(O[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=O)C>CCOCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OCCOCOC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCOCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 138 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time=30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether solution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][S:25]([N:28]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:29])(=[O:27])=[O:26]>>[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][S:25]([N:28]([C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:35][CH:36]=1)[CH3:29])(=[O:27])=[O:26]
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CN(C)CCS(=O)(=O)N(C)c1ccc(N)cc1
Product: CN(C)CCS(=O)(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 39 from 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino]-aniline.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:10])=[S:9])([CH3:3])[CH3:2].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18]CC)=[O:17]>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[S:9][C:15]([C:16]([OH:18])=[O:17])=[C:21]([CH3:23])[N:10]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)Oc1cccc(C(N)=S)c1
Solvent: CCO
Product: Cc1nc(-c2cccc(OC(C)C)c2)sc1C(=O)O
Temperature: 70 °C
Yield: 64.6 %

Procedure:
390 mg of 3-Isopropoxythiobenzamide was dissolved in 5 ml of ethanol, 360 mg of ethyl 2-chloroacetoacetate was added to the solution, and the mixture was heated under reflux for five hours. After the reaction mixture was cooled, it was concentrated and subjected to silica gel chromatography (eluent, hexane: ethyl acetate=9:1) to separate an intended product (490 mg). The resulting oily substance was dissolved in 5 ml of ethanol, 10 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was heated at 70° C. for one hour. After the completion of the reaction, ethanol was removed by distillation and the residue was neutralized with 1N hydrochloric acid. The precipitated crystal was collected by filtration and recrystallized from a 50% aqueous ethanol solution to give 358 mg of 2-(3-isopropoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 65%).
Reaction SMILES: B(Br)(Br)Br.ClCCl.C([O:15][C@@H:16]1[C@@H:20]([CH2:21][O:22]CC2C=CC=CC=2)[S:19][CH:18]([N:30]2[CH:37]=[CH:36][C:34]([NH2:35])=[N:33][C:31]2=[O:32])[C@H:17]1[F:38])C1C=CC=CC=1.CCCCCC>ClCCl>[F:38][C@H:17]1[C@H:16]([OH:15])[C@@H:20]([CH2:21][OH:22])[S:19][CH:18]1[N:30]1[CH:37]=[CH:36][C:34]([NH2:35])=[N:33][C:31]1=[O:32]
Reactant: Nc1ccn(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2F)c(=O)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
0.065 mL of a 1 mol/L boron tribromide-dichloromethane solution was added to a solution of 9.6 mg of 1-(3,5-bis-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in 1 mL of dichloromethane under cooling on ice. While the temperature was gradually increased to room temperature, the obtained mixture was stirred for 2 hours. Thereafter, hexane was added to the reaction mixture, and a solid was then collected by filtration. The obtained solid was washed with toluene and ethyl acetate, so as to obtain 5.3 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[N:28][CH:29]=1)#[N:23].N1CCC(C(O)=O)CC1>>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:12][N:11]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH2:35][CH2:34]2)=[O:37])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Agent: O=C(O)C1CCNCC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 141-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as an orange oil. MS m/e: 524.3 [M]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8]/[C:9](/[NH:18]C(=O)OC(C)(C)C)=[N:10]/C(=O)OC(C)(C)C)=[CH:6][C:5]([CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:27]2([CH3:34])[CH3:33])=[CH:4][N:3]=1.Cl>C(Cl)Cl>[CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:18])=[NH:10])=[CH:6][C:5]([CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][C:27]2([CH3:34])[CH3:33])=[CH:4][N:3]=1
Reactant: Cc1ncc(C2CCN(C)CC2(C)C)cc1N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(C2CCN(C)CC2(C)C)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.2 %

Procedure:
To a solution of di-tert-butyl ((Z)-{[2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-yl]amino}methylylidene)biscarbamate (0.78 g, 1.60 mmol) in DCM (10 mL) was added hydrochloric acid (4.0 M in 1,4-dioxane, 20 mL). The reaction mixture was allowed to stir at rt overnight. The reaction mixture was concentrated to give the hydrochloride salt of N-[2-methyl-5-(1,3,3-trimethylpiperidin-4-yl)pyridine-3-yl]guanidine (750 mg, 110%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH2:32][CH2:31][C:30]([NH:29][C:25]1[CH:24]=[C:23]([C:9]2[S:10][C:11]([C:12]3[NH:16][CH:15]=[N:14][N:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:28]=[CH:27][N:26]=1)=[O:33]
Reactant: C=CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Reactant: COC[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H]1CCCN1CCC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of N-(4-(4-phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl)pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (120 mg, 1.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction solution was cooled to room temperature, and diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated, extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→50/50) to give the title compound (60 mg, 62%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1.C(OC(C1C(C(=O)NC2C=CC(C)=C(I)C=2)CN(C2C=CC=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:29]([O:28][C:26]([CH:25]1[CH2:31][CH2:32][N:22]([C:2]2[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][N:15]4[CH2:18][CH3:19])=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH2:23][CH2:24]1)=[O:27])[CH3:30]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Reactant: CCOC(=O)C1CCNCC1
Agent: CCOC(=O)C1CCN(c2ccccn2)CC1C(=O)Nc1ccc(C)c(I)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(CC)c4c3)cn2)CC1

Procedure:
5′-(1-Ethyl-1H-indol-6-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C24H28N4O3 [M+H]+: 421.2234. Found: 421.2234.
Reaction SMILES: [N:1]1([C:7](=[O:31])[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.O>C(Cl)Cl>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([N:16]([C:13]2[CH:12]=[CH:11][C:10]([CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:31])=[CH:15][CH:14]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:20][CH:19]=2)(=[O:49])=[O:48])=[CH:45][CH:46]=1
Reactant: O=C(C=Cc1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1)N1CCOCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(C=CC(=O)N3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1-morpholin-4-yl-3-{4-[4-(tetrahydro-pyran-2-yloxy)benzylamino]-phenyl}-prop-2-en-1-one (0.115 g, 0.27 mmol) and triethylamine (0.100 mL, 0.72 mmol) in 3 mL methylene chloride was added 4-methoxybenzenesulfonyl chloride (0.065 g, 0.31 mmol). The reaction mixture was stirred at room temperature for 60 h. Water was added and the aqueous solution was washed with methylene chloride (3×). The combined organic layers were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (50% ethyl acetate/hexanes) gave the title compound of Step B.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][O:52]C(C)(OC)C)[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][OH:52])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1

Procedure:
A solution of 0.812 g of the product of Step A, 4 ml of acetone and 1 ml of N hydrochloric acid was stirred at room temperature for 3 hours and 1 ml of an aqueous solution of 1M sodium bicarbonate, 10 ml of water and 5 ml of ethyl acetate were added thereto to obtain 0.551 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate melting at ≃200° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:23])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[OH-:26].[K+]>COCCOC>[Cl:23][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:26])=[O:4])=[CH:6][NH:7]2)=[CH:12][C:11]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=1
Reactant: CCOc1ccc(-c2cc3c(C(=O)C(Cl)(Cl)Cl)c[nH]c3cc2Cl)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: COCCOC
Product: CCOc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
To a solution of 2,2,2-trichloro-1-(6-chloro-5-(4-ethoxyphenyl)-1H-indol-3-yl)ethanone (70.0 mg, 0.17 mmol) in DME (1 mL) was added 1N KOH (0.71 mmol, 0.71 mL). The reaction mixture was stirred at room temperature for 12 hours, and concentrated in vacuo. The crude material was diluted with water (5 mL), and acidified to pH 2.5 with 1N HCl to form a white precipitate. The precipitate was filtered, washed with water (20 mL) and dried under vacuum to provide the title compound (37 mg, 70%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[C:17]([O:13][CH2:12][C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@@H:8]([OH:15])[C@@H:9]1[OH:14])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5 g, 20 mmol) in pyridine (150 mL) was added a solution of benzoyl chloride (3.4 g, 24 mmol) in dichloromethane (10 mL) at 0° C. within 10 minutes, and then stirred for 5 hours at 0° C. in an ice/salt bath. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 2% 5% methanol in dichloromethane to afford the title compound as an off-white solid (4.5 g, 63%). (ES, m/z): [M+H]+ 353.0; 1H NMR (300 MHz, CD3OD) δ 8.07-8.01 (m, 2H), 7.99-7.40 (m, 3H), 6.43 (d, J=6.6 Hz, 1H), 4.88-4.85 (m, 1H), 4.63-4.45 (m, 1H), 4.19-4.15 (m, 1H), 3.99-3.93 (m, 2H), 3.36-3.32 (m, 1H), 3.06 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:15][O:16][NH2:17]>>[CH3:15][O:16][N:17]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Reactant: CON
Agent: Cl
Product: CON=C(C(=O)O)c1ccc(O)c(Cl)c1

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.) and O-methylhydroxylamine hydrochloride (2.74 g.) were reacted according to a similar manner to that of Preparation (5-3)(a) to give oil of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)(=O)C>C(O)C.[Fe]>[CH3:1][C:2]1[S:3][C:4]2[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cccc([N+](=O)[O-])c2s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2cccc(N)c2s1
Yield: 68.5 %

Procedure:
To a solution of 3.8 g of the product from Example 6 and 8.1 g of glacial acetic acid in 56 mL absolute ethanol at reflux temperature was added 3.8 g of iron powder in small portions. The reaction mixture was heated at reflux temperature for about 36 hours, and was then cooled and filtered. The filtrate was concentrated in vacuo and the residue treated with several mL cold water to give a solid. Filtration and drying gave 2.2 g of the title compound as a tan-colored solid, m.p. 100°-101° C.; NMR (CDCl3): δ 2.8 (3H, s), 3.9 (2H, br s), 6.65 (1H, d, J=8 Hz), 7.2 (1H, t, J=8 Hz), 7.5 (1H, d, J=8 Hz).