Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([O:22][CH3:23])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([O:22][CH3:23])[CH:14]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)cc2OC)oc1C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 4-fluoro-2-methoxyphenylboronic acid (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 51%) as a white solid.
Reaction SMILES: [O:1]=[C:2]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:1]=[C:2]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](=[O:33])(=[O:34])[NH2:32])=[CH:27][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)CN(CCCCCC(=O)Nc1ccc(S(N)(=O)=O)cc1)Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NC(=O)CCCCCN(CC(=O)O)Cc2ccccn2)cc1

Procedure:
[Re(CO)3][2-((6-oxo-6-(4-sulfamoylphenylamino)hexyl)(pyridin-2-ylmethyl)amino)acetic acid]. A solution of tert-butyl 2-((6-oxo-6-(4-sulfamoylphenylamino) hexyl)(pyridin-2-ylmethyl)amino)acetate (70 mg, 0.14 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure to give 2-((6-oxo-6-(4-sulfamoylphenylamino)hexyl)(pyridin-2-ylmethyl)amino) acetic acid. A solution of the above isolated product, 2-((6-oxo-6-(4-sulfamoylphenylamino) hexyl)(pyridin-2-ylmethyl)amino)acetic acid, [NEt4]2[ReBr3(CO)3] (108 mg, 0.14 mmol) and potassium carbonate (30 mg) in MeOH (4.0 mL) and water (1.0 mL) was stirred at 100° C. for 4 h in a sealed pressure tube. The reaction mixture was purified by Amberchrom™ eluting with MeOH/H2O to give the title compound (64 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.13 (td, J=7.6, 1.2 Hz, 1H), 7.76-7.55 (m, 5H), 7.56 (t, J=6.4 Hz, 1H), 7.23 (s, 2H), 4.74 (d, J=16.0 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 3.82 (d, J=16.8 Hz, 1H), 3.54-3.40 (m, 2H), 3.38 (d, J=16.8 Hz, 1H), 2.38 (t, J=7.4 Hz, 2H), 1.76-1.31 (m, 6H); ESMS m/z: 705.3 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Li].CS(O[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH2:30][CH:29]=1)(=O)=O>C1COCC1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH2:30][CH:29]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CS(=O)(=O)OCCCCCCCC1=CC1
Agent: [Li]C
Solvent: C1CCOC1
Product: C1=C(CCCCCCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Diphenylamine (0.42 g, 2.5 mmol) in 10 ml of THF was cooled to −78° C. and treated with 1.6 ml (1.4M, 2.2 mmol) methyllithium. 1-(7-Methanesulfonyloxyheptyl)-cyclopropene was added, the bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction was held for 5.5 hours, then quenched with water. Ether and water were added to the reaction mixture and the phases were separated. The ether phase was washed with water twice, washed with brine, dried over magnesium sulfate and stripped. The product was chromatographed to give 80 mg of 7-(diphenylamino)-1-heptylcyclopropene as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19].O.O.[Sn](Cl)Cl>CCO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccncc2Br)cc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 80 °C
Yield: 111.6 %

Procedure:
3-Bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine (0.414 g, 1.25 mmol) was dissolved in EtOH (30 mL). Tin (II) chloride dihydrate (1.129 g, 5.00 mmol) was added and the mixture was heated at 80° C. for 411. The solvent was removed under reduced pressure and the residue quenched with saturated aqueous NaHCO3. The mixture was diluted with EtOAc and filtered through Celite®. The Celite® bed was washed with water (2×) and EtOAc (2×), and the filtrate was extracted with EtOAc (2×). The combined organic extracts were dried and evaporated to yield 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 112% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.33 (d, 1H), 7.28-7.23 (m, 1H), 6.76-6.71 (m, 2H), 5.56 (br s, 2H); MS (ESI) m/z: 301.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.[CH2:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[C:32]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[N:31]1)[CH3:29].C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:28]([N:30]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)(=[O:21])=[O:20])[C:9]([C:11]4[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=4)=[CH:10][C:3]=23)[C:32]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[N:31]1)[CH3:29]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2cccc(CO)c2)cc2c(Br)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CO)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
In a large pressure bottle (˜1 L) was added {3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanol (22.75 g, 51.3 mMol), 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21.0 g of a ˜85% pure lot, 52.0 mMol, Intermediate 5), dioxane (400 mL), aq. sat. NaHCO3 (120 mL), and Pd(PPh3)4 (1.5 g, 1.3 mMol). The reaction was purged with N2, capped, and stirred at 110° C. for 16 h. After cooling to RT the reaction was concentrated under vacuum, taken up in EtOAc, washed with H2O, brine, dried (Mg2SO4), filtered, and evaporated to dryness under vacuum. Purification by flash chromatography by silica gel (20 to 30% EtOAc/CH2Cl2) gave the title compound (26.90 g, 90%) as a yellow solid: MS (ES) m/e 580.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.15 (app. d, 2H), 7.89 (d, J=7.3 Hz, 2H), 7.74 (t, J=7.5 Hz, 1H), 7.61 (app. t, J=7.8 Hz, 2H), 7.54 (app. d, 2H), 7.39-7.43 (m, 2H), 7.32-7.36 (m, 2H), 7.06 (d, J=5.1 Hz, 1H), 6.52 (s, 1H), 5.31 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.3 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.3 Hz, 3H).
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C(N(CC)CC)C>[Br:7][C:8]1[CH:13]=[C:12]([C:14]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[O:16])[CH:11]=[CH:10][N:9]=1
Reactant: CCNCC
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (1.07 g) was added dropwise to a solution of 2-bromo-4-pyridinecarboxylic acid (2 g) and triethylamine (1 g) at 0°. The mixture was stirred at room temperature for 1 h, diethylamine (3 ml) was added dropwise and the resulting suspension was stirred vigorously for 2 h. The precipitate was collected by filtration and washed with water (20 ml) to give the title compound as a white solid (1.55 g), m.p. 200°-203°.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1.Cl.C(=O)(O)[O-].[Na+]>>[CH3:11][S:10][C:6]1[N:5]=[C:4]([CH:3]=[O:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(OC)c1ccnc(SC)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1nccc(C=O)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3×150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1 (incorporated by reference), pg 67.
Reaction SMILES: ClC1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@@H:9]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[CH:4][N:3]=1.C(NCC)C.C1COCC1.[CH3:42][N:43]([CH:45]=O)[CH3:44]>>[CH3:44][N:43]([CH3:42])[C:45]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@@H:9]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc(Cl)nc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCNCC
Product: CN(C)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A glass microwave reaction vessel was charged with (S)-6-chloro-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (50 mg, 0.109 mmol, example 135), DMF (1 mL), and 2 M diethylamine in THF (0.054 mL, 0.109 mmol). The reaction mixture was stirred and heated in a Biotage Initiator at 100° C. for 30 minutes. This was repeated at 150° C. for 30 minutes at a time until LC-MS indicated complete consumption of starting material. The reaction product was purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with a linear gradient of 20% to 70% MeCN (0.1% TFA) in water (0.1% TFA) over 20 minutes. The desired fractions were poured into 10% Na2CO3 and extracted with DCM (3×5 mL). The combined DCM layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ ppm 8.86 (d, J=3.8 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.02 (d, J=7.9 Hz, 2H), 7.92 (dd, J=9.1, 2.5 Hz, 1H), 7.54 (s, 4H), 7.45 (dd, J=7.7, 4.4 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.49 (d, J=9.2 Hz, 1H), 3.14 (s, 6H) MS (ESI pos. ion) m/z: 469.0 (M+H).
Reaction SMILES: [C:1]([C:6]1[C:17]([O:18][CH3:19])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[C:1]([C:6]1[C:17]([O:18][CH3:19])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([C:13]([OH:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2nc(CO)n(C)c2cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1OC

Procedure:
In a manner analogous to that described in Example 12, 5.2 g of 5-butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol are oxidised with 4.5 g of potassium permanganate to give 5-butyryl-6-methoxy-1-methyl-benzimidazole-2-carboxylic acid with a melting point above 85° (decomposition)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:18][C:16](=O)[C:15](=[C:19]=[O:20])[CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[NH2:22][NH2:23]>C(O)C>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:18][C:16](=[N:22][NH2:23])[C:15](=[C:19]=[O:20])[CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1cc(C2CC(=C=O)C(=O)O2)cc(OC)c1OC
Solvent: CCO
Solvent: O
Product: COc1cc(C2CC(=C=O)C(=NN)O2)cc(OC)c1OC

Procedure:
11.2 g (0.04 mol) of 4-(3,4,5-trimethoxyphenyl)-carbonyl-γ-butyrolactone and 2 ml (0.04 mol) of hydrazine hydrate are stirred in 60 ml of ethanol at room temperature for 1 hour and the precipitate is filtered off with suction.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[Cl:5][C:6]1[C:11]2[C:12](=[O:24])[N:13]3[CH2:23][CH2:22][C@H:14]3[C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20]#[N:21])[C:10]=2[CH:9]=[CH:8][C:7]=1[F:25]>CO>[Cl:5][C:6]1[C:11]2[C:12](=[O:24])[N:13]3[CH2:23][CH2:22][C@H:14]3[C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20](=[N:3][OH:4])[NH2:21])[C:10]=2[CH:9]=[CH:8][C:7]=1[F:25]
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
3.1 g (134.8 mmol) of sodium were dissolved in 140 ml of methanol. 10 g (145 mmol) of hydroxylamine hydrochloride and 28.6 g (94.5 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were added in succession at room temperature. The suspension was stirred at room temperature overnight, cooled to 0° during 30 min., the crystals were filtered off, suspended in 50 ml of water and filtered off. The methanol solution was concentrated, whereupon the residue was suspended in 30 ml of water and the crystals were filtered off. By drying the combined crystallizate there were obtained 30.94 g (97%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime of m.p. 236°-238°.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:4].O.[OH-].[Li+]>O1CCOCC1.O.Cl>[C:19]1([S:16]([NH:15][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:3]([OH:4])=[O:2])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Temperature: 160 °C

Procedure:
2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 4, 0.68 g) was dissolved in dioxane (12 mL) and a solution of lithium hydroxide monohydrate (0.6 g) in water (6 mL) was added. The mixture was heated by microwave irradiation at 160° C. for 15 minutes then diluted with 1N hydrochloric acid. The product was extracted into DCM and the organic solution was separated, dried with magnesium sulfate, filtered and the filtrate was concentrated under vacuum to give the title compound as a white powder.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH2:44])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47].[C:48](OC(=O)C)(=[O:50])[CH3:49].O>CO>[CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH:44][C:48]([CH3:49])=[O:50])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@@H]1[C@@H](N)[C@@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)O[C@H](C)[C@@H]1O
Solvent: O
Solvent: CO
Product: CO[C@H]1[C@@H](O)[C@@H](C)O[C@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)[C@@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of elsamicin A (65.4 mg) and acetic anhydride (0.1 ml) in dry methanol (2 ml) was stirred at room temperature for 1 hour. Water (1 ml) was added and the mixture was evaporated in vacuo to give a yellow oil, which was purified by column chromatography on silica gel to give 70.5 mg (100%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 93.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), methanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C. with stirring by use of a mechanical stirrer. After the temperature became stable, a 20% aqueous solution of sodium hydroxide was added to the mixture so as to adjust the pH of the mixture at 9.0-9.3. When four hours had elapsed after the reaction started, 20% sodium hydroxide (96.7 g) was added. Liquid chromatographic analysis revealed that the reaction mixture contained 69.1 g of p-cyanobenzoic acid (yield 94%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added to the mixture to lower the pH to 3.1. The mixture was heated again to 82° C., and methanol was added thereto until the mixture dissolved. The resultant mixture was cooled for crystallization, to thereby obtain 64.8 g of p-cyanobenzoic acid crystal (purity 97.5%, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>CN(C=O)C>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([NH:15][C:13]([NH2:14])=[N:12][C:10]([C:3]3[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=3)=[O:11])[CH2:17]2)[CH:33]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN2CCC[C@H](NC(N)=NC(=O)c3nc(Cl)c(N)nc3N)C2)c1

Procedure:
A mixture of 1.17 g (4.5 mmol) 4-Aminomethyl-4-phenethyl-piperidine-1-carbocylic acid tert-butyl ester (intermediate 3), 1 mg (4.9 mmol) (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester and 125 μl triethylamin in 50 ml DMF/iso-propanol (1:3) is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure. Then 50 ml 25% TFA in dicholoromethane is added and the mixture is stirred for 2 h at room temperature and evaporated. The residue is treated with excess HCl in methanol and evaporated again to yield 430 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine. Step B: 100 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine, 125 μl triethylamine and 62 mg 3-bromomethyl-benzoic acid methyl ester in 3 ml DMF were stirred at room temperature for 6 h. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1(C)[O:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4](=[O:18])[O:3]1.C1(C)C=CC=CC=1.C[O-].[Na+].Cl>C(O)C>[OH:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:18]
Reactant: CC(C)(C)OC(=O)CC(=O)CC1OC(C)(C)OC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(=O)CC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of tert.-butyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-oxobutanoate (16.30 g, 60.08 mmol) in a mixed solvent of toluene (120.0 ml) and ethanol (60.0 ml), sodium methoxide (4.91 g, 79.10 mmol) was dropwise added at 0° C. in an argon atmosphere and stirred for 30 minutes. After dropwise adding 1N hydrochloric acid (80.5 ml), the mixture was stirred at 0° C. for 10 minutes. After evaporating off the most of the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate and washed with a saturated saline and a phosphate buffer (pH 7.0). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=2:1) to give pure 1-ethyl 6-tert.-butyl 2-hydroxy-4-oxoadipate (14.02 g, 53.85 mmol). Yield, 89.6%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH:34]3[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[O:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:28][CH2:29][CH:30]([N:33]([CH:34]3[CH2:36][CH2:35]3)[C:14]([C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[F:17])[O:13][N:12]=3)=[O:16])[CH2:31][CH2:32]2)[O:24][N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)on3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid and [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.29 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH:5]([CH3:12])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16].CN(C)C>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH:5]([CH3:12])[S:4]1)=[O:16]
Reactant: CN=C=O
Reactant: CC1SC(=NO)C(C)(C)NC1=O
Agent: CN(C)C
Product: CNC(=O)ON=C1SC(C)C(=O)NC1(C)C

Procedure:
Utilizing the procedure of Example V, 2-oximino-3,3,6-trimethyltetrahydro-1,4-thiazin-5-one was reacted with methyl isocyanate in the presence of trimethylamine to yield 3 g of 2-[O-(methylcarbamoyl)oximino]-3,3,6-trimethyltetrahydro-1,4-thiazin-5-one, m.p. 190°-191° C. IR spectrum supported the proposed structure.