Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:22][C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=3)=O)=[C:10]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH:11]=2)[C:6]([CH3:35])([CH3:34])[C:5]1=[O:36])([CH3:3])[CH3:2]>C(O)(=O)C>[CH3:33][N:27]1[C:28](=[O:32])[C:29]([CH3:31])=[CH:30][C:25]([C:23]2[N:13]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:10]3[C:9]([N:22]=2)=[CH:8][C:7]2[C:6]([CH3:35])([CH3:34])[C:5](=[O:36])[N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=3)=[CH:26]1
Reactant: Cc1cc(C(=O)Nc2cc3c(cc2N[C@@H](C)c2ccccc2)N(C(C)C)C(=O)C3(C)C)cn(C)c1=O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc3cc4c(cc3n2[C@@H](C)c2ccccc2)N(C(C)C)C(=O)C4(C)C)cn(C)c1=O
Temperature: 120 °C
Reaction time: 7 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid [1-isopropyl-3,3-dimethyl-2-oxo-6-((S)-1-phenyl-ethylamino)-2,3-dihydro-1H-indol-5-yl]-amide I-2′ (100 mg; 0.21 mmol) is dissolved in 2 ml acetic acid and stirred at 120° C. for 7 h. The solvent is evaporated and the crude product is purified using reversed phase chromatography (Method: prep. HPLC2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13](=[O:24])[N:14]([C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=4)[CH2:15][CH2:16][C:11]=3[C:10]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]1(=[O:35])[NH:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH-].[NH4+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13](=[O:24])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([N:34]5[CH2:33][CH2:32][CH2:31][CH2:30][C:29]5=[O:35])=[CH:19][CH:18]=4)[CH2:15][CH2:16][C:11]=3[C:10]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Reactant: O=C1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Temperature: 120 °C
Yield: 45 %

Procedure:
Part B. In a round bottomed flask were combined 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (1.00 g, 1.89 mmol), δ-valerolactam (0.36 g, 3.79 mmol), anhydrous powdered potassium carbonate (1.05 g, 7.58 mmol), cuprous iodide (0.072 g, 0.38 mmol), and 1,10-phenanthroline (0.068 g, 0.38 mmol). The flask was purged with argon and degassed methylsulfoxide (10 mL) was added before heating to 120° C. Upon completion of the reaction, as judged by TLC or LC/MS, the reaction was cooled to ambient temperature and 50 mL each of 3M ammonium hydroxide and dichloromethane were added. The phases were separated and the aqueous extracted with an additional 30 mL of dichloromethane. The combined dichloromethane extracts are washed successively four times with water and once with brine. The solution was dried over sodium sulfate, filtered, and evaporated to give an oil that was purified by flash column chromatography eluting with ethylacetate to give 0.424 g (45%) of 1-(3-chloro-phenyl)-3-methanesulfonyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one as a colorless solid. The material may be recrystallized from acetonitrile. 1H NMR (DMSO-d6) δ 7.79 (t, 1H, J=2 Hz), 7.63-7.49 (m, 3H), 7.32 (ab q, 4H, J=21.9 Hz), 4.10 (t, 2H, J=6 Hz), 3.58 (t, 2H, J=5 Hz), 3.36 (s, 3H), 3.19 (t, 2H, J=6 Hz), 2.37 (t, 2H, J=5 Hz), 1.83 (m, 4H). LC/MS (ES+): 498.9/500.9 (Cl pattern) (>95% pure by ELSD).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:28])[C:9]=1[C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=[C:14]2[CH:13]=1)=[O:4].O.[OH-].[Li+].Cl>CO.O>[CH3:28][N:8]1[C:9]([C:10](=[O:27])[NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:14]3[CH:13]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]1
Reactant: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A white suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester (2.37 g, 6.3 mmol) and lithium hydroxide monohydrate (291 mg, 6.93 mmol) in methanol (100 ml) and water (20 ml) is stirred for 5/4 hr at 70° C. giving after 20 min a colorless solution. The methanol is removed in vacuo, the residue is diluted with water and the cooled aqueous solution is neutralized with 2N aqueous hydrochloric acid (3.46 ml, 6.03 mmol). The solid is collected by filtration and dried affording 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (2.21 g, 97%) as a white solid. mp.: >300° C. MS: m/z=361.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:50][OH:51]>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:50][OH:51])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 29.4 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[4-(4-pyridinyl)-1-piperidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 32) (311 mg, 0.68 mmol) and N-methylmorpholine (83 μl, 0.75 mmol) in N,N-dimethylformamide (15 ml) was cooled to 0° C., treated dropwise with isobutyl chloroformate (98 μl, 0.75 mmol) and the resulting solution was stirred at 0° C. for 45 minutes. Hydroxylamine hydrochloride (142 mg, 2.05 mmol) was then added followed by further N-methylmorpholine (226 μl, 2.05 mmol) and the mixture was stirred for 18 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLC to afford a residue that was partitioned between ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to yield the title compound as a white solid (94 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([O:30]C(CC(C)C)=O)[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43].[Li][Al](OC)OC>O.O1CCCC1.C(O)=O>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(OC(=O)CC(C)C)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: [Li][Al](OC)OC
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: -50 °C

Procedure:
This example describes reduction of ansamitocins with LiAl(OMe)2.5H1.5 using water followed by aqueous formic acid quench. Ansamitocins (1.0 g, 1.57 mmol) were weighed into a three necked flask equipped with a thermometer. Tetrahydrofuran (5 mL) was added to the flask with stirring, and the flask was cooled in a −50° C. cooling bath. Once the contents of the flask reached −35° C., a solution of 0.67 M LiAl(OMe)3H in tetrahydrofuran (18.5 mL, 12.4 mmol) was added dropwise by syringe using a syringe pump. The temperature of the reaction was maintained between −30° C. and −40° C. throughout the addition. After addition was complete the reaction was stirred for 2 hours at between −32° C. and −37° C. Deionized water (2.5 mL) was added dropwise to the −35° C. reaction to give a basic quenched mixture. The basic quenched mixture was analyzed by the thin layer chromatography assay described in example 6. The compound of Formula (I) was detected. After 30 min the basic quenched mixture was analyzed again by the thin layer chromatography method. The compound of Formula (I) was no longer detected. Aqueous formic acid (deionized water, 5 mL, and 88% formic acid, 0.62 mL) was then added to the flask followed by 22 mL of ethyl acetate. The cooling unit was turned off and the mixture was allowed to slowly warm to room temperature. The pH of the mixture was checked with pH paper and found to be approximately pH 6. The mixture was vacuum filtered, and solvent was removed by rotary evaporation under vacuum. Butyl acetate (5 mL) was added to the residue, the solvent was then evaporated to remove any remaining water. The residue was purified by silica chromatography using a mobile phase of dichloromethane:methanol 95:5 (v:v) to give 0.63 g of maytansinol (71% yield by weight).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[CH3:19][N:20]1[CH:24]=[C:23](I)[CH:22]=[C:21]1[C:26]([O:28][CH3:29])=[O:27]>>[CH3:19][N:20]1[CH:24]=[C:23]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:22]=[C:21]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1cc(I)cn1C
Product: COC(=O)c1cc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cn1C

Procedure:
Following the basic procedure of Example 11(d), by reacting 2.9 g (12 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 3.2 g (12.1 mmol) of methyl N-methyl-4-iodo-2-pyrrolecarboxylate, 2.8 g (61%) of the expected ester, with a melting point of 150°-152° C., were recovered by trituration in isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:28][C:27]2([CH2:31][N:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:29]2)[CH2:26]1)=[O:24].[C:39](O)(=[O:42])[CH2:40][CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:39](=[O:42])[CH2:40][CH3:41])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:28][C:27]2([CH2:31][N:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:29]2)[CH2:26]1)=[O:24]
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CC4(C3)CN(c3ccc(F)cc3)C4)cnc3c(S(N)(=O)=O)cnn23)c1
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CC4(C3)CN(c3ccc(F)cc3)C4)cnc12
Yield: 54.5 %

Procedure:
Using 7-(2-chloro-5-methylphenylamino)-6-[6-(4-fluorophenyl)-2,6-diazaspiro[3,3]heptane-2-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.045 g, 0.081 mmol) obtained in step 2 and propionic acid (0.030 mL, 0.405 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.027 g, 54%) was obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.C([Li])CCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C>C1COCC1>[C:10]([O:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:2]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:3][N:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(Br)s1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl 5-bromothiazol-2-yl(isopropyl)carbamate (7.5 g, 23.3 mmol) in THF (50 mL) was added n-butyllithium (1.6 M in hexane, 21.8 mL) dropwise at −78° C. The solution turned orange. The solution was stirred at −78° C. for minutes before 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.49 g, 34.9 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours then warmed to room temperature. The reaction was quenched with 1:1 ammonium chloride/water (50 mL). The resulted mixture was extracted with ethyl acetate (100 mL). The organic layer was separated, washed with water, brine and concentrated. To the brown solid residue was added hexane (30 mL). The mixture was filtered and the filter cake was washed with hexane (20 mL) and dried to give as a yellow solid (4.17 g, 48% yield). LCMS (Conditions C): 3.21 min (RT); (M+H)+=247.12 (40%), 245.12 (50%), 233.10 (75%), 231.10 (100%). 1H NMR, 400 MHz, CDCl3: δ 7.95 (s, 1 H), 5.37 (m, 1 H), 1.60 (s, 9 H), 1.44 (d, 6.7 Hz, 6 H), 1.34 (s, 12 H).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:23]([C:24]([O:26]C)=[O:25])=[C:22]3[C:17]([CH:18]4[CH2:28][CH:19]4[CH2:20][O:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:6]([CH:29]=[CH2:30])[CH:5]=1>O1CCOCC1.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:23]([C:24]([OH:26])=[O:25])=[C:22]3[C:17]([CH:18]4[CH2:28][CH:19]4[CH2:20][O:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[C:6]([CH:29]=[CH2:30])[CH:5]=1
Reactant: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Lithium hydroxide (0.101 g) was added to a solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 75, 0.150 g) in a mixture of dioxane (3 mL) and water (0.6 mL) and the mixture was irradiated in the microwave at 130° C. for 30 minutes. After cooling, the mixture evaporated to dryness and the residue was acidified by addition of 10% aqueous citric acid (2 mL), extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and DCM with a gradient of 0-10% to give (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.0.35 g) as a glass.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C([O:4][C@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:10]=1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:14]([N:13]1[C:9]([NH:8][C:6](=[O:7])[C@H:5]([OH:4])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:12]1)[CH3:15]
Reactant: CCn1nc(-c2ccncc2)cc1NC(=O)[C@@H](Cc1ccccc1)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1nc(-c2ccncc2)cc1NC(=O)[C@H](O)Cc1ccccc1
Reaction time: 1 h

Procedure:
To (R)-1-(1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-yl acetate (438 mg, 1157 μmol) was added K2CO3 (320 mg, 2315 μmol), followed by MeOH. After 1 hr, the reaction was completed by LC/MS. The reaction was concentrated and worked up with brine and 30% isopropanol in CHCl3. The crude material was purified by trituration with dichloromethane followed by filtration.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH:4]([OH:14])[CH2:5][N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[N:7]1.[H][H]>[Pd].C(O)C>[NH2:11][C:9]1[CH:8]=[N:7][N:6]([CH2:5][CH:4]([OH:14])[CH2:3][N:2]([CH3:1])[CH3:15])[CH:10]=1
Reactant: [H][H]
Reactant: CN(C)CC(O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC(O)Cn1cc(N)cn1
Yield: 92 %

Procedure:
1-(dimethylamino)-3-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (253 mg, 1.18 mmol) and palladium on carbon (10%, 25 mg) were stirred in ethanol (5 mL) under a balloon of hydrogen for 24 h. The palladium was removed by filtration through celite and the solution was concentrated to afford 1-(4-amino-1H-pyrazol-1-yl)-3-(dimethylamino)propan-2-ol as a brown oil (200 mg), which was used crude in the following reaction.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:26])=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:6])C.O.O.[OH-].[Li+]>>[CH2:28]([NH:27][C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:7]([C:5](=[O:6])[C:4]([OH:40])=[O:3])[C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1)=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)OCC)c2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)O)c2ccc(C(F)(F)F)cc2)cc1
Yield: 89 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) using ethyl{{4-[(dodecylamino)carbonyl]benzyl}[4-(trifluoromethyl)phenyl]amino}(oxo)acetate and lithium hydroxide dihydrate gave the title compound as a white solid (89%). 1H NMR (DMSO-d6, 300 MHz) δ 8.39 (s, 1H), 7.77 (m, 4H), 7.45 (d, 2H, J=7.9 Hz), 7.27 (d, 2H, J=7.5 Hz), 5.07 (s, 2H), 3.20 (m, 2H), 1.48 (m, 2H), 1.28 (m, 18H), 0.84 (t, 3H, J=5.9 Hz). M−(APCI): 489.2 (M-CO2). HPLC (Condition A), Rt: 6.44 min (HPLC purity: 97.4%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:21]=1[CH2:22]Br>CC(C)=O>[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:21]=1[CH2:22][O:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([OH:7])[CH:17]=1
Reactant: COc1cc(Br)c(CBr)cc1OC
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2cc(OC)c(OC)cc2Br)cc1O
Temperature: 80 °C

Procedure:
Potassium carbonate (1.12 g) was added to a solution of methyl 2,4-dihydroxybenzoate (454 mg) and 2-bromo-4,5-dimethoxybenzyl bromide (1.0 g) in dry acetone (80 ml). The reaction mixture was heated to reflux at 80° C. for 4 hours. The solvents were removed under vacuum and the residue was re-dissolved in DCM and washed with water (3×). The organic layer was passed through a hydrophobic frit and concentrated under vacuum. The crude residue was purified by chromatography on silica gel, eluting with petrol and increasing amounts of ethyl acetate.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=O.[C:21](C1NC=CN=1)([C:23]1[NH:24][CH:25]=[CH:26]N=1)=O.C(NCC)C>CN(C)C=O>[CH2:23]([N:24]([CH2:25][CH3:26])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:1])[CH3:21]
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A mixture of 10.0 g (0.037 mol) of d-lysergic acid in 500 ml of dry dimethyl formamide (DMF), under argon, was treated with 9.0 g of carbonyl diimidazole and stirred at room temperature for 1 hour. The reaction was then treated with 38 ml of diethylamine and stirred at room temperature overnight. The reaction was concentrated under reduced pressure. The residue was taken up in 500 ml of methylene chloride and washed with 500 ml of water. Insoluble material was removed by filtration and the layers were separated. The organic portion was washed with 250 ml of saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on 800 g of silica gel using 3% methanol in methylene chloride to yield 9.0 g (75%) of d-lysergic acid diethylamide (LSD) as a light brown amorphous solid after evaporation of the solvents.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][C:20]4[CH:24]=[CH:23][O:22][N:21]=4)[O:15][C:14]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3]1.Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>ClCCl.CO.O>[N:28](=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][C:20]4[CH:24]=[CH:23][O:22][N:21]=4)[O:15][C:14]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3]1)[OH:29]
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(=NO)C2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
3-(4-(3-Oxo-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (124 mg, 0.34 mmol) was dissolved in a mixture of dichloromethane (10 ml) and MeOH (10 ml), and treated with a solution of hydroxylamine hydrochloride (220 mg, 3.17 mmol) and sodium acetate (500 mg) in water (2 ml). After stirring at ambient temperature for 4 hours, solvents were evaporated, and the residue triturated with water (10 ml), solid filtered and dried to give the desired product (118 mg) as a single isomer of unknown geometry. MS (ESP): 377 (MH+) for C17H17FN4O5.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccccc2)cc1
Yield: 92.6 %

Procedure:
According to General Procedure A, a mixture 4-chlorobenzonitrile (69 mg, 0.50 mmol), phenylboronic acid (91 mg, 0.75 mmol), CsF (228 mg, 1.50 mmol), Pd(OAc)2 (2 mg, 0.01 mmol) and 12f (8 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to reflux, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (5% Et2O in hexanes, silica gel) gave 51c (83 mg, 92%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.69 (q, 4H, J=6 Hz), 7.61-7.57 (m, 2H), 7.52-7.40 (m, 3H); 13C NMR (75.5 MHz, CDCl3) δ 145.6, 139.1, 132.5, 129.0, 128.6, 127.6, 127.1, 118.8, 110.8.