Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:14].CC(O[CH2:19][C:20]1[CH2:37][S:36][C@@H:23]2[C@H:24]([NH:27][C:28]([CH2:30][C:31]3[S:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[C:25](=[O:26])[N:22]2[C:21]=1[C:38]([OH:40])=[O:39])=O.[H-].[Na+]>O>[Na+:14].[S:35]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:30][C:28]([NH:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:38]([O-:40])=[O:39])=[C:20]([CH2:19][C:1](=[S:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:37][S:36][C@H:23]12)=[O:29]
Reactant: OC(=S)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(CC(=S)c3ccccc3)CS[C@H]12
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Thiobenzoic acid (1.41 g, 10.2 mmol) and sodium bicarbonate (0.857 g, 10.2 mmol) were stirred in 30 ml of H2O and heated to 50° C. The mixture was filtered through silica gel, and the filtrate was added to cephalothin (1.43 g, 3.4 mmol) in 20 ml of H2O. The reaction mixture was stirred for 20 hours at 50° C. 7-Thiophenylacetamido-3-thiobenzoylmethyl-3-cephem-4-carboxylic acid (0.791 g) was collected by filtration. 50 mg of this material was dissolved in DMF (2 ml). Sodium hydride (4.4 mg. 0.11 mmol) was added, and the mixture was stirred for two hours, filtered, and dried under vacuum. The residue was dissolved in water, refiltered and lyophilized to yield pure 7-thiophenylacetamido-3-thiobenzoylmethyl-3-cephem-4-carboxylate sodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2N(C3C=CC=CN=3)N=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:32]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:31]=3)[N:33]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1ccnc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccnc(C(F)(F)F)c2)n1

Procedure:
500 mg (1.53 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 358 mg (1.68 mmol) of 2-trifluoromethylpyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 444 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22])=[CH:7]2)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([C:21]([NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22])=[CH:7]2
Reactant: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2n1CCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CCc1ccccc1

Procedure:
50 mg (0.13 mmol) of 5-nitro-N-phenyl-1-(2-phenylethyl)-1H-indole-2-carboxamide from Example XLIX are initially charged in 7 ml of ethyl acetate and 7 ml of ethanol. 49 mg (0.78 mmol) of ammonium formate and 14 mg of palladium on activated carbon are added. The mixture is heated to reflux, and at 50° C. gas evolves. After 4 hours at reflux, the mixture is cooled and filtered through kieselguhr, which is then washed with 500 ml of ethanol. The solvent is removed under reduced pressure and the residue is dried. This gives 115 mg of a white solid which still contains inorganic salts and which is reacted further without purification.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-:13].[Na+]>O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[OH:13]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1O
Yield: 8.9 %

Procedure:
50 g of 2-amino-5-nitroanisole, 50 g of sodium hydroxide were dissolved in 450 ml of water. The resultant mixture was heated under reflux for 3 hours and then ice-cooled. Precipicated crystals were collected by filtration, followed by dissolution in water. The thus-prepared solution was neutralized with 6 N hydrochloric acid and crystals thus precipitated were collected by filtration. The crystals were dissolved in chloroform. The resultant solution was washed with water and dried over anhydrous sodium sulfate. By concentrating the chloroform layer under reduced pressure, 4.5 g of 2-methoxy-4-nitrophenol were obtained as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](=[S:37])[NH2:36]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:37][C:35]([C:34]([CH3:39])([CH3:38])[CH3:33])=[N:36][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cc(C(=O)Cc2ccnc(Cl)n2)ccc1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: O
Product: C=CCOC(=O)Nc1cc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 2-propen-1-yl {5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (35 g, 100.3 mmol in DMA, 500 mL), NBS (17.8 g, 100.3 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then 2,2-dimethylpropanethioamide (13 g, 111 mmol) was added at 0° C. The mixture was stirred at 80° C. for 2 h. The mixture was poured into water and extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound (36 g, 80.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.24-8.31 (m, 2H), 7.09-7.18 (m, 2H), 7.01 (d, J=5.5 Hz, 1H), 6.92-6.98 (br, 1H), 5.87-5.97 (m, 1H), 5.31-5.37 (m, 1H), 5.24-5.28 (m, 1H), 4.61-4.65 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Oc4ccccc4)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3[nH]c4cccc(Oc5ccccc5)c4c3CC2)cc1

Procedure:
A solution of 3-benzoyl-10-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.55 g, 1.45 mmol) in tetrahydrofuran (30.0 mL) and lithium aluminum hydride (0.56 g, 14.5 mmol) was reacted in a manner similar to Preparation 11 to afford 0.47 g (87%) of colorless solid as the desired product: mp 168-170° C. (CH2Cl2/hexane); 1H NMR (400 MHz, DMSO-d6) δ 11.0; 7.34-7.21, 7.10, 7.01, 6.94, 6.84, 6.47, 3.69, 2.89-2.87, 2.84-2.81, 2.78-2.75, 2.65-2.62; 13C NMR (100.6 MHz, DMSO-d6) δ 158.5, 147.8, 139.2, 137.4, 136.9, 1295.6, 128.4, 128.1, 126.7, 121.8, 120.5, 120.3, 116.4, 110.2, 109.3, 107.4, 60.2, 55.4, 53.3, 27.6, 24.8; MS (EI) m/z 368 (M+); HRMS cacld for C25H24N2O+H: 369.1967, found: 369.1961; Anal. Calcd. for C25H24N2O: C, 81.49; H, 6.57; N, 7.60. Found: C, 81.12; H, 6.70; N, 7.53.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]>CO.O1CCOCC1.[C].[Pd]>[C:1]([CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CC#N)C1
Yield: 79 %

Procedure:
tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (823 mg, 4.24 mmol) in a mixture of methanol (20 mL) and 1,4-dioxane (10 mL) was stirred with 5% palladium-carbon (129 mg) for one day under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (657 mg, yield 79%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([N:11]=[N+]=[N-])[CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C@H:6]1[O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.[Ni]>[C:1]([NH:4][C@@H:5]1[C@@H:10]([NH2:11])[CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C@H:6]1[O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Agent: [Ni]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1
Reaction time: 6.5 h

Procedure:
100 g (0.295 mol) ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate were dissolved in 800 ml ethanol and placed in a 21 steel autoclave together with 34 g Raney Nickel (Degussa) in 200 ml ethanol. The autoclave was closed rinsed twice with nitrogen and then set under 2 bar hydrogen pressure. Hydrogenation took place at a temperature of 20-25° C. under mechanical stirring a 1000 rpm until, after all the starting material had reacted, also the content of the “2-azido-5-amino intermediate” was ≦0.01% area (GC measurement) which was about 5-8 h. However, it was found that due to this “overhydrogenation” the “cyclohexene double bond” became hydrogenated, too.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[CH:7]=[C:8](/[C:12](/[CH3:19])=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:10][CH:11]=1)#[N:5].CO>O1CCCC1.O>[C:4]([C:6]1[CH:7]=[C:8](/[C:12](/[CH3:19])=[CH:13]/[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: CCOC(=O)/C=C(\C)c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\C(=O)O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of lithium hydroxide monohydrate (10.8 g, 0.26 mol) in tetrahydrofuran (100 ml) and water (100 ml) was added crude ethyl (E)-3-(3-cyanophenyl)-2-butenoate (Preparation 31) in tetrahydrofuran (150 ml). The resultant mixture was made homogeneous by the addition of methanol (approx. 50 ml), and then stirred at room temperature for 16 h. The mixture was concentrated in vacuo and acidified with 2N hydrochloric acid, following which a solid precipitated. The solid was collected by suction filtration, washing with cold water. The solid was then dried and recrystallised from acetonitrile. From the first crop, 15.8 g (49% over 2 steps) of the pure E-isomer was isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]#[CH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a vigorously stirred suspension of piperazine-1-carboxylic acid tert-butyl ester (4.2 g, 22.5 mmol) and K2CO3 (1.2 eq, 27 mmol, 3.7 g) was added propargyl bromide (80 wt % in toluene, 1.2 eq, 27 mmol) dropwise via syringe over 20 minutes. The mixture was stirred at room temperature overnight (about 20 hours), concentrated in vacuo and partitioned between water and EtOAc. The organic-phase was washed twice with water, dried over MgSO4, filtered and evaporated to afford a clear yellow oil that partially solidified upon prolonged standing and was used directly without further purification. 1H NMR (400 MHz, CDCl3) d 1.47 (s, 9H), 2.28 (t, 1H), 2.54 (m, 4H), 3.34 (d, 2H, J=2.4 Hz), 3.49 (m, 4H). MS: m/z 225 (M+1).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([S:19]([NH:22][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:24])(=[O:21])=[O:20])=[CH:11][C:10]=1[N+:30]([O-])=[O:31])([C:3]([O:5]CC)=O)=[O:2]>CN(C)C=O.[Pt]>[C:23]([NH:22][S:19]([C:12]1[CH:11]=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:5])[N:30]2[OH:31])=[CH:14][C:13]=1[C:15]([F:16])([F:18])[F:17])(=[O:20])=[O:21])([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:24]
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)c(S(=O)(=O)NC(=O)C(=O)OCC)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)NS(=O)(=O)c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Yield: 59.7 %

Procedure:
A solution of 1-ethoxalylamino-4-ethoxalylaminosulfonyl-2-nitro-5-trifluoromethylbenzene (24.6 g, 50 mmol) in 200 ml of N,N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of 1 g of 5% platinum on carbon for 2 h. The catalyst was filtered off and washed with N,N-dimethylformamide. The filtrate was evaporated to dryness and the gummy residue was refluxed with 100 ml of ethanol for about 20 min. The mixture was cooled and the precipitated product was collected by filtration and washed with ethanol and ether to give 12.7 g (59%) of the title compound. M.p. 222° C. decomp. (DSC); IR (KBr): 1685 cm-1 ; 1H-NMR (DMSO-d6): 1.25 (t,J=7Hz, 3H, CH3), 4.23 (q,J=7Hz, 2H, CH2), 7.67 (s, 1H, ArH), 8.30 (s, 1H, ArH), 10.8 (broad s, 2H, exchangeable), 12.5 (broad s, 1H, exchangeable).
Reaction SMILES: [OH-:1].[K+].[OH-].[Na+].S([C:9]1[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=[O:14])(O)(=O)=O>>[OH:1][C:9]1[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc(O)cc1C(=O)O
Temperature: 0 °C

Procedure:
In a stainless steel beaker with a steel stirrer a mixture of 300 g KOH (5.36 mole), 150 g NaOH (3.75 mole), 120 g of a 50% aqueous solution of 4-sulfophthalic acid (~0.25 mol) was heated for 4 hr on an oil bath. It was then cooled such that it remained molten and poured into 600 ml ice + water. With cooling it was neutralized to pH 9.0 without noting any precipitate of m-hydroxybenzoic acid by-product. It was then acidified, evaporated to dryness in a rotary evaporator and extracted in a Soxhlet to separate the soluble product from the insoluble inorganics. Crude yield 26 g (59%, M.P. 175°-180° C. Recrystallized from ~2 vol boiling water. Yield 19.5 g (44%), M.P. 201°-3° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@H:28]2[O:30][C@@H:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1.[ClH:47].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@@H:28]([OH:30])[C@@H:29]([Cl:47])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: Cl
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3.8mg of Cryptophycin 1 in 1.5 mL of 2:1 1,2-dimethoxyethane/water was added 9 μL 1N HCl. The solution was allowed to stir at room temperature for 4 h, neutralized with potassium carbonate, and evaporated. The residue was partitioned between water and CH2Cl2. The CH2Cl2 -soluble material was purified by reversed-phase HPLC to obtain 3.3 mg of pure Cryptophycin 8.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])[CH3:20]>>[CH2:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:24])[CH3:20]
Reactant: CCc1ccccc1C(=O)O
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: CCc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-ethylbenzoic acid. MS (ESI) mass calcd. for C23H24N4O, 372.46; m/z found, 373.2 [M+H]+.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].O>CN(C=O)C>[C:8]([NH:1][C@H:2]([C:5]([O:7][CH2:21][CH3:22])=[O:6])[CH2:3][OH:4])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Ser-OH (0.3 g, 1.46 mmol, 1 eq) in dry DMF (4 ml) at 0° C., dry K2CO3 (0.22 g, 1.6 mmol, 1.1 eq) was added. The resulting white suspension was stirred for 15 minute and ethyl iodide (0.68 g, 0.35 ml, 4.38 mmol, 3 eq) was dropwise added. The cooling was removed and reaction mixture was stirred at room temperature under N2 for 24 h. To the formed white emulsion H2O was added, and the mixture extracted by EtOAc. The combined organic layer was washed by H2O and then brine, and dried over MgSO4. The solvent was evaporated and the obtained oil was dried overnight in high vacuum. Yield of the pure F—0.27 g (79%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([NH2:14])[CH:13]=1)(C)(C)C.[C:18]([O:22][C:23]([N:25]([CH2:34][C:35](O)=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[N:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:34][C:35](=[O:36])[NH:14][C:12]1[CH:13]=[C:8]([CH2:7][OH:6])[CH:9]=[CH:10][C:11]=1[CH3:15])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1N
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Product: Cc1ccc(CO)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Yield: 58.8 %

Procedure:
Prepared according to the method of Example 3b), from 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-phenylamine (2.0 g) and [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (2.30 g) to give the sub-title product (1.9 g) as a white solid.
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=O.[H-].[Na+].[S:18]1[CH:22]=[C:21]([CH:23]=O)[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]1=2>C1COCC1>[S:18]1[CH:22]=[C:21](/[CH:23]=[CH:6]/[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]1=2
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: O=Cc1csc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/c1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate (6.13 g, 25.6 mmol) was added dropwise via syringe to a stirred suspension of sodium hydride (1.02 g, 25.6 mmol) in anhydrous THF (75 ml) at 0° C. The reaction was warmed to room temperature and was stirred for 1 h. After cooling to 0° C., benzo[b]thiophene-3-carbaldehyde (3.78 g, 23.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hr. The reaction was quenched with 100 mL aqueous HCl (0.1 N) and extracted with ethyl acetate (250 ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo and triturated with hexane to give (E)-3-benzo[b]thiophen-3-yl-N-methoxy-N-methyl-acrylamide (5.38 g, 93%) as a yellow solid. 1H NMR (500 MHz, CDCl3) 8.06-8.01 (2H, 2 superimposed d, J=8.24, 15.87 Hz), 7.89 (1H, d, J=7.94 Hz), 7.78 (1H, s), 7.47 (1H, t, J=7.93 Hz), 7.41 (1H, t, J=8.24 Hz), 7.13 (1H, d, J=15.87 Hz), 3.79 (3H, s), 3.34 (3H, s); MS m/e 248.07 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Ethyl 3-[{[4-({[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}(methyl)amino]-propanoate (0.2 g) synthesized in the above-mentioned (2) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.18 g, 94%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=3)[N:10]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.CO.[OH-].[Na+].Cl>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[N:10]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1ccnc(C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Temperature: 80 °C
Yield: 98.6 %

Procedure:
In a sealed flask was added ethyl 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylate (420 mg, 0.802 mmol), MeOH (6 ml), and sodium hydroxide (1N in water, 4 ml, 4.00 mmol). The resulting mixture was then heated for 60 min at a temperature of 80° C. with stirring. The mixture was then neutralized with HCl (2N in water), diluted with 10% isopropanol in chloroform, washed with water, dried with sodium sulfate, filtered, and concentrated to afford 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (392 mg, 0.791 mmol) as a light yellow solid. The crude product was progressed to the next step without purification.