Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]([C@:19]12[CH2:54][C:53](=[O:55])[C:52]([CH:56]([CH3:58])[CH3:57])=[C:20]1[C@@H:21]1[C@@:34]([CH3:37])([CH2:35][CH2:36]2)[C@@:33]2([CH3:38])[C@@H:24]([C@:25]3([CH3:51])[C@@H:30]([CH2:31][CH2:32]2)[C:29]([CH3:40])([CH3:39])[C@@H:28]([O:41][C:42](=[O:50])[CH2:43][C:44]([CH3:49])([CH3:48])[C:45]([OH:47])=[O:46])[CH2:27][CH2:26]3)[CH2:23][CH2:22]1)[CH2:6][N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(=O)C.[OH-].[K+].Cl>C(O)C.C1(C)C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]([CH2:6][C@H:5]([C@:19]23[CH2:54][C:53](=[O:55])[C:52]([CH:56]([CH3:57])[CH3:58])=[C:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:51])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:39])([CH3:40])[C@@H:28]([O:41][C:42](=[O:50])[CH2:43][C:44]([CH3:48])([CH3:49])[C:45]([OH:47])=[O:46])[CH2:27][CH2:26]4)[CH2:23][CH2:22]2)[OH:4])[C:8](=[O:10])[CH3:9])=[CH:17][CH:16]=1
Reactant: CC(=O)O[C@H](CN(Cc1ccc(Cl)cc1)C(C)=O)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N(Cc1ccc(Cl)cc1)C[C@@H](O)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution of 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-(N-(4-chlorobenzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (72) (150 mg, 0.182 mmol) in ethanol (2 mL) and toluene (2 mL) was added potassium hydroxide (40.9 mg, 0.729 mmol). The reaction mixture was stirred at rt for min. The reaction mixture was neutralized with aqueous 1 N HCl to pH=7 and concentrated to obtain a residue. The residue was extracted with DCM, washed with water and dried to yield the crude product which was purified by preparative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(4-chlorobenzyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (73) (40 mg, 28%) as a white solid. Compound exists as a mixture of rotomers; 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 7.52-7.14 (m, 4H), 5.03-3.77 (m, 5H), 3.39-2.80 (m, 3H), 2.62-2.54 (m, 1H), 2.27 (t, J=17.2 Hz, 1H), 2.20-0.58 (m, 51H);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])#[N:2].OO.Cl([O-])=[O:15].[Na+]>O.C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]([OH:15])=[O:9])#[N:2]
Reactant: [O-][Cl+][O-]
Reactant: N#Cc1ccc(F)c(C=O)c1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
NaH2PO4 (87 mg, 0.724 mmol) in water (3.5 mL) was added to a solution of 5-cyano-2-fluorobenzaldehyde (500 mg, 3.35 mmol) in acetonitrile (7 mL), followed by 30% H2O2 (0.31 mL). Sodium chlorite (434 mg, 4.8 mmol) in water (3.5 mL) was added dropwise to this reaction mixture at 0° C. The mixture was stirred at room temperature for 1 h, quenched with aqueous sodium sulfite solution at 0° C. and then acidified with 1.5N HCl solution. The aqueous solution was extracted with EtOAc and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-cyano-2-fluorobenzoic acid (500 mg, yield 90%). 1H NMR (300 MHz, DMSO-d6) δ 13.79 (br s, 1H), 8.30-8.27 (dd, J=6.6 Hz, 2.2 Hz, 1H), 8.17-8.12 (ddd, J=8.6 Hz, 4.4 Hz, 2.3 Hz, 1H), 7.60-7.53 (dd, J=10.5 Hz, 8.8 Hz, 1H). MS (ESI) m/z: Calculated for C8H4FNO2: 165.02. found: 163.6 (M−H)−.
Reaction SMILES: [C:1]([O:10]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH2:14][NH2:15]>C(O)C>[C:1]([NH:14][NH2:15])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NN
Reactant: CCCCCCCC(=O)OCC
Solvent: O
Solvent: CCO
Product: CCCCCCCC(=O)NN
Reaction time: 15 h

Procedure:
Production of the spacer-gel derivative: Ethyl caprylate was converted into the corresponding hydrazide by hydrazinolysis, by initially admixing 10 ml. of this ethyl ester with 10 ml. of 98% hydrazine hydrate. Ethanol (22 ml.) was added as solvent, until the reaction mixture cleared, following which the solution was left at room temperature for 15 hours. The crystallized out resulting caprylhydrazide was filtered off and washed with ice water and then with aqueous methanol (1:1) of room temperature.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:8][CH:7]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:8][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Reaction time: 4 h

Procedure:
A 15 ml round bottom flask charged with 4-(2-(4-(4-hydroxybutyl)phenyl)ethoxy) quinazoline (0.25 g, 0.77 mmol) is dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate/hexanes) to give the product.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:9](Br)[C:10]#[CH:11].O>CN(C)C=O>[CH2:11]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:10]#[CH:9]
Reactant: O=C(O)CCS
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-mercaptopropionic acid (15 ml) in dry dimethylformamide (250 ml) was stirred at 0° , under nitrogen. Sodium hydride (10.2 g; 80% dispersion in oil) was added carefully and the mixture was stirred at 40° for 1 hour. The mixture was cooled to 0° C. and propargyl bromide (60 g; 80% in toluene) was added dropwise. The mixture was stirred at 20° for 3 hours and then at 80° for 1 hour. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether, and the extracts washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The resulting oil (30 g) (mainly prop-2-ynyl 3-(prop-2-ynylthio)propionate) was added to a solution of sodium hydroxide (8.0 g) in water (100 ml) and methanol (100 ml) and the mixture was stirred at 20° for 24 hours. The mixture was extracted with diethyl ether and the aqueous solution was acidified with hydrochloric acid. The acidic mixture was extracted with diethyl ether and the ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 3-(Prop-2-ynylthio) propionic acid was obtained as a red oil (12.0 g) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1cccc(Cl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cccc(Cl)c3)c2c1

Procedure:
The titled compound (20 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 3-chlorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: Nc1cccnc1
Reactant: O=C=NCCCl
Product: O=C(NCCCl)Nc1cccnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 150 g of 3-aminopyridine dissolved in 1000 ml of tuluene, 176 g of 2-chloroethylisocyanate was added dropwise over 30 minutes under cooling. After stirring at room temperature for 5 hours, the precipitated crystals were collected by filtration to give 318 g of N-(2-chloroethyl)-N'-(3-pyridyl) urea.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2nc(-c3ccccc3)oc2n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 80 mg. of 5-amino-2-phenyloxazolo[5,4-b]pyridine in 1 ml. of pyridine was treated with 0.07 ml. of benzoyl chloride. After standing 1 hour the mixture was diluted with ice-water. The precipitate was collected and recrystallized from methanol to give 5-benzoylamino-2-phenyloxazolo[5,4-b]pyridine, m.p. 191°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH2:12]N(C)C)[C:3]=12.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[C:11]([CH2:12][C:16]#[N:17])[C:3]=12
Reactant: CN(C)Cc1c[nH]c2c(Cl)ncc(Br)c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c[nH]c2c(Cl)ncc(Br)c12

Procedure:
A solution of [(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]dimethylamine from Step A (195 mg, 0.676 mmol) and potassium cyanide (440 mg, 6.76 mmol) in DMF (0.5 mL) and H2O (0.5 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=272 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][CH2:12][C:11](=O)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29])=[CH:23][CH:22]=1>O1CCOCC1.CCOC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][C:11]([NH:29][CH2:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)([CH3:31])[CH3:30])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(c2cccc(Cl)c2)=NN1
Reactant: CC(C)(CN)c1ccc(F)cc1
Agent: O=[Mn]=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(CNc1cnc(-c2cccc(Cl)c2)nn1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
To a solution of 3-(3-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (6.0 g, 29 mmol) dissolved in dioxane (75 mL) was added MnO2 (10 g, 120 mmol). The mixture was stirred at 90° C. for 18 h. After filtering through diatomaceous earth and rinsing with hot dioxane, the combined organics were evaporated to dryness in vacuo. The crude residue (⅓ was used) was dissolved in POCl3 (10 mL, 108 mmol) and heated to 70° C. for 2.5 h. The mixture was allowed to cool to rt and evaporated to dryness in vacuo. The residue was dissolved in EtOAc/ether (1:1) and washed with 1 M NaOH. The organic phase was evaporated to dryness and dissolved in NMP (5.0 mL) in a microwave vial. Potassium carbonate (1.0 g) was added followed by (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.0 g, 12 mmol), and the mixture was heated in a microwave reactor to 165° C. for 20 min. The solution was diluted with EtOAc and washed with saturated NaCl (4×), dried over Na2SO4, and evaporated to dryness. Purification using silica gel chromatography (0-35% EtOAc/hexanes) gave the desired product (430 mg) as an orange film.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:18][CH2:17]1.O>O1CCCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([N:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)[CH:23]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1ncc(Cl)c(Nc2cccc(N3CCOCC3)c2)n1
Reaction time: 8 h

Procedure:
2,4,5-Trichloropyrimidine (0.960 g, 5.2 mmol) was dissolved in tetrahydrofuran (20 mL). Potassium carbonate (1.20 g, 8.70 mmol) was added, followed by 3-morpholinoaniline (0.875 g, 4.90 mmol). After stirring overnight, water (30 mL) and dichloromethane (30 mL) were added, the phases separated and the aqueous layer extracted once with dichloromethane (30 mL). The combined organic fractions were dried over sodium sulfate, concentrated onto silica gel and chromatographed (120 g SiO2, 0-50% EA:Hex). (2,5-Dichloro-pyrimidin-4-yl)-(3-morpholin-4-yl-phenyl)-amine was isolated as an off-white solid (1.16 g, 73%). m.p.=142-145° C.; LCMS (m/e) 325 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.38 (s, 1H), 7.28 (m, 1H), 7.21 (s, 1H), 7.01 (d, 1H, J=7.8 Hz), 6.75 (d, 1H, J=8.4 Hz), 3.88 (t, 4H, J=4.8 Hz), 3.21 (t, 4H, J=4.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:29][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C(c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 110 °C
Yield: 69.5 %

Procedure:
A stirred suspension of (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (400 mg, Example 1e), 4-chlorobenzamide (185 mg), copper(I) iodide (20 mg), N,N′-dimethylglycine (20 mg) and potassium phosphate (1.05 g) in DMSO (2 ml) in a sealed tube was heated at 110° C. overnight. The mixture was then cooled to room temperature and was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-[4-(4-chloro-benzoylamino)-phenyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (297 mg, 69%) as a white solid. MS (ISP): 450.2 ([{37Cl}M+NH4]+), 448.2 ([{35Cl}M+NH4]+), 433.2 ([{37Cl}M+H]+), 431.2 ([{35Cl}M+H]+), 377.2 ([{37Cl}M+H—C4H8]+), 375.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[C:14]1([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][C:22]([C:30]([OH:32])=[O:31])([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CO>[C:14]1([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][C:22]([C:30]([O:32][CH3:8])=[O:31])([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C12CC3CC(C1)CC(c1ccccc1)(C3)C2
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12CC3CC(C1)CC(c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Trimethylsilyldiazomethane 2M solution in hexane (8.15 mL, 16.31 mmol) was added dropwise to a stirred solution of 3-phenyl-1-adamantanecarboxylic acid (2.09 g, 8.15 mmol, CAS 37589-22-3) in toluene (20 mL) and methanol (10 mL) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 60 minutes. The reaction mixture was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (2.140 g, 97%) as a colourless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:13])=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][C:26]([NH:11][C:10]2[CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=[CH:8][C:9]=2[CH3:13])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCC(=O)O
Reactant: Cc1ccc(-c2ccoc2)cc1N
Product: Cc1ccc(-c2ccoc2)cc1NC(=O)CCCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-(furan-3-yl)-2-methylaniline was reacted with the 5-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-5oxopentanoic acid obtained in Example 31-(i) to give 5-chloro-2-[(5-([5-(furan-3-yl)-2-methylphenyl]amino)-5-oxopentanoyl)amino]benzoic acid.methyl ester (yield: 73%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[C:11]([Br:14])[CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1)=[O:22])(=[O:3])[CH3:2]>ClCCl.CO>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[C:11]([Br:14])[CH:12]=2)[NH:7][C:6]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1)=[O:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)n2)c(NC(C)=O)c2cc(Br)c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1c(C(=O)c2cccc(C)n2)[nH]c2cc(Cl)c(Br)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-5-bromo-6-chloro-1-(ethoxycarbonyl)-2-(6-methylpyridine-2-carbonyl)indole (step 2). m.p.: 234-236° C. (dichloromethane/methanol) 1H-NMR (DMSO-d6) δ: 12.01 (1H, br s), 10.26 (1H, br s), 8.21 (1H, s), 7.98 (1H, t, J=7.7 Hz), 7.86 (1H, d, J=7.7 Hz), 7.85 (1H, s), 7.57 (1H, d, J=7.7 Hz), 2.66 (3H, s), 1.99 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1.33 h
Yield: 35.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (15.0 g) in anisole (15 ml) was added 2,2,2-trifluoroacetic acid (60 ml) under ice-cooling with stirring, and the stirring was continued at 10° to 15° C. for 80 minutes. After the reaction mixture was poured into diisopropyl ether (600 ml), the insoluble substance was collected by filtration and then dried. This substance (11.2 g) was dissolved in an aqueous solution of sodium bicarbonate so as to adjust the resultant solution to pH 6.0, and then chromatographed on alumina (44.8 ml) using 5% aqueous sodium acetate as an eluent. The fractions containing the desired compound were collected and evaporated to dryness to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3.55 g), mp>250° C.
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[CH:21]=[C:20]([CH3:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[F:32])[CH2:25][N:22]1[CH:21]=[C:20]([CH3:34])[C:11]2[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]3=[C:9]([OH:8])[C:10]=2[C:23]1=[O:24]
Reactant: Cc1cn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-4,8-dimethyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (0.20 g, 0.40 mmol) and 5% Pd/C (40 mg) in a mixture ethanol (100 mL) and acetic acid (11 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 1 hr. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue subjected to reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provided the title product.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:48])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:49][CH3:50])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:51](C1C=C(C(C)C)C=C(C(C)C)C=1S(NN)(=O)=O)(C)C.C(N(CC)CC)C>CO>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:48])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:51])[C:13]([O:49][CH3:50])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Yield: 6 %

Procedure:
To a solution of olefin N-[17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)-sulfonamide (63, 100 mg, 0.139 mmole) in MeOH (3.0 mL) heated at 80° C., was added 2,4,6-triisopropylbenzene sulfonohydrazide (TrisNHNH2) and triethylamine portion wise over several hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and a saturated solution of NaHCO3, successively washed with HCl 1N and brine, dried (MgSO4), filtered and evaporated. Purification by flash chromatography (gradient of AcOEt/CH2Cl2, 0:1 to 1:9) followed by recrystallization from isopropylether/petroleum ether, and then preparative HPLC afforded 6 mg (6%) of the title product (59) as a white powder: m/z=724 (M+H)+. 1H NMR (CDCl3): 0.90-1.70 (m, 21H), 1.95-2.03 (m, 2H), 2.25-2.35 (m, 2H), 2.63-2.68 (m, 2H), 2.99 (m, 1H), 3.22 (m, 1H), 3.41 (m, 1H), 3.96 (m, 5H), 4.15 (d, J=15 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 5.53 (m, 1H), 6.57 (s, 1H), 7.05 (s, 1H), 7.12 (dd, J=2.5 Hz, 9.1 Hz, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.56 (s, 1H), 7.93 (d, J=9.1 Hz, 1H), 10.8 (br s, 1H).