Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][N:15]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: C1CCOC1
Product: CN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (350 mL), 113c (10.0 g, 32.2 mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred at room temperature for 72 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was stirred with a mixture of ethyl acetate (75 mL) and 10% aqueous potassium carbonate (75 mL). The aqueous layer was separated and extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with 10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford 113d in 97% yield (5.70 g) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 6.62 (s, 1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52 (s, 3H); MS (ESI+) m/z 183.0 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C([NH:16][C@@H:17]1[C:22](=[O:23])[O:21][C:19](=[O:20])[CH2:18]1)=O.N[C@H](C(O)=O)CC1C=CC=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:5][C:22](=[O:23])[C@H:17]([CH2:18][C:19](=[O:20])[OH:21])[NH2:16]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
In a known process which does not use L-phenylalanine methyl ester, N-formyl-L-aspartic anhydride is subjected to a condensation reaction with L-phenylalanine in acetic acid and then the formyl group is removed in the presence of an aqueous hydrogen halide solution. The reaction product is subsequently esterified by treating with water, alcohol and the aqueous hydrogen halide solution, and α-L-aspartyl-L-phenylalanine methyl ester is isolated in the form of its hydrogen halide salt (U.S. Pat. No. 3,933,781).
Reaction SMILES: [CH3:1][NH2:2].[F:3][CH2:4][O:5][N:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:8](OC)=[O:9]>CO>[F:3][CH2:4][O:5][N:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:8]([NH:2][CH3:1])=[O:9]
Reactant: CN
Reactant: COC(=O)C(=NOCF)c1ccccc1COc1ccccc1C
Solvent: CO
Product: CNC(=O)C(=NOCF)c1ccccc1COc1ccccc1C
Reaction time: 24 h

Procedure:
2 ml of 33% methylamine solution (in ethanol) are added to a solution of 1.02 g of 2-(2-methylphenoxymethyl)-phenylglyoxalic acid methyl ester O-fluoromethyl oxime in 30 ml of methanol and the reaction mixture is left to stand for 24 hours. Concentration by evaporation is then carried out in vacuo and the concentrate is crystallised from hexane. Pure 2-(2-methylphenoxymethyl)-phenylglyoxalic acid N-methylamide O-fluoromethyl oxime is obtained; m.p. 86°-88° C.
Reaction SMILES: [C:1]([C:3]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:19]([F:22])([F:21])[F:20])[CH:4]=1)#[N:2].OO.C(=O)([O-])[O-:26].[K+].[K+]>CS(C)=O>[NH2:2][C:1]([C:3]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:19]([F:21])([F:20])[F:22])[CH:4]=1)=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C#N
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-cyano-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (257 mg, 0.818 mmol) was dissolved in DMSO (2 mL) and was cooled in a cold water bath. 30% Aqueous hydrogen peroxide (0.2 mL) and potassium carbonate (38 mg, 0.275 mmol) was added and the mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate then filtered and concentrated to afford methyl 4-aminocarbonyl-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (quantitative yield) as a yellow oil. MS (EI) for C15H19F3N2O3: 333 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[C:42]([O:49][C@H:50]([CH2:52][CH:53]=[CH2:54])[CH3:51])[CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:43]5[CH:44]=[CH:45][C:40]([F:39])=[CH:41][C:42]=5[O:49][C@H:50]([CH2:52][CH:53]=[CH2:54])[CH3:51])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(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: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.27 g, 0.462 mmol, 1 equiv) and (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid (207 mg, 0.924 mmol, 2 equiv) in DMF (5 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (53 mg, 0.046 mmol, 0.1 equiv) and 2 M Na2CO3 (0.46 mL, 0.924 mmol, 2 equiv). The reaction was heated at 90° C. for 2.5 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (210 mg, 66%) as a viscous yellow oil. LCMS (ESI, M+1): 684.35.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C@H:11]1[C:16](=O)[NH:15][CH2:14][C:13](=O)[NH:12]1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([C@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[C@@H]1NC(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CNCCN1
Temperature: 65 °C
Reaction time: 17 h
Yield: 51 %

Procedure:
Lithium aluminum hydride(1 M solution in THF, 40 mL, 40.0 mmol) was added drop wise to solution of (S)-2-tert-butylpiperazin-3,6-dione (1.5 g, 8.82 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 days and at 65° C. for 17 h, then cooled to 0° C. and quenched sequentially with H2O (1.7 mL), 10% NaOH (2.2 mL) and H2O (3.4 mL). Ether (100 mL) was added to the reaction mixture, and stirring was continued for 1.5 h. The solid was filtered, the filtrate was concentrated and purified by column chromatography (silica gel, 33% EtOAc in hexanes) to afford (S)-2-tert-butylpiperazine (0.64 g, 52%) as a clear oil. 1H NMR and MS consistent.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2cnccc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1ccncc1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To a suspension of tert-butyl 1-[4-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-3-pyridyl]piperidine-4-carboxylate trifluoroacetic acetate (prepared according to a methodology similar to the one described in Example 1) (101 mg, 0.1773 mmol) in DCM (5 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and diethyl ether (×2) to give title compound as a beige solid (98% Yield, di-TFA salt). 1H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 9.58 (dd, 1H), 8.91 (d, 1H), 8.86 (d, 1H), 8.68 (s, 1H), 8.56 (d, 1H), 6.92 (s, 2H), 3.10 (d, 2H), 2.99-2.82 (m, 2H), 2.53-2.50 (m, 1H), 2.15-1.93 (m, 4H); 19F NMR (471 MHz, DMSO) δ −74.10, −151.83; LC-MS ES+: 400.0.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=O>>[CH2:42]([N:41]([CH2:44][CH3:45])[CH2:39][CH2:38][O:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[CH:4][CH:3]=1)[CH3:43]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: CCN(CC)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 28.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-diethylacetamide (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.1 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[CH3:27][NH2:28]>C(O)C.O>[CH3:27][NH:28][CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Solvent: O
Solvent: CCO
Product: CNCC(O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
Using an analogous reaction procedure to that described in Example 33, a mixture of 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine and 33% methylamine in ethanol and NHP was stirred over 2 days at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The product so obtained was washed with water and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-(3-methylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino) pyrimidine is 46% yield, m.p. 88°-90° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:10][C:3]=12.Cl.[Br:17][C:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)(Cl)Cl>[Br:17][C:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:19]1[CH2:20][CH2:21][N:22]([C:12](=[O:14])[C:11]([C:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[NH:10][CH:9]=2)=[O:15])[CH2:23][CH2:24]1
Reactant: BrC(=C1CCNCC1)c1ccccc1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Cl)ccnc12
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(=O)N1CCC(=C(Br)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12
Reaction time: 48 h

Procedure:
To a solution of (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-oxo-acetic acid (191 mg, 0.87 mmol), 4-(bromophenylmethylene)-piperidine hydrochloride salt (245 mg, 0.85 mmol) and diisopropylethylamine (440 mg, 3.4 mmol) in chloroform (10 mL) was added BOPCl (261 mg, 1.02 mmol). The reaction solution was stirred two days, treated with additional diisopropylethylamine (440 mg, 3.4 mmol) and BOPCl (130 mg, 0.50 mmol) and stirred three days. The reaction mixture was concentrated, dissolved into MeOH and purified by preparative HPLC to yield title compound shown (293 mg, 0.64 mmol, 75%) as a white solid.
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4](=O)[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.CCN(CC)CC.Cl.[NH2:33][OH:34]>O1CCOCC1>[C:15]([O:14][C:13]([NH:12][CH:3]([C:4](=[N:33][OH:34])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:1])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccncc1)C(=O)N1CCCC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1)C(=NO)c1ccncc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a stirred solution of tert-butyl(±)-1,3-dioxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate TTA 08120 (0.20 g, 0.60 mmol) in 10 mL of dioxane were added Et3N (125 μl, 0.90 mmol) and hydroxylamine hydrochloride (65 mg, 0.90 mmol). The mixture was stirred 2 h at 110° C. in a sealed tube then dioxane was evaporated. The obtained residue was purified by column chromatography (SiO2, CH2Cl2:MeOH=9:1 to 97:3) to give (±)-2-tert-butyloxycarbonylamino-3-(hydroxyimino)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one TTA 08160 (100 mg, 48% yield) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[C@H:6]2[CH:5]=[C:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.S(=O)(=O)(O)O>O>[OH:20][C:18]([C@@H:4]1[CH:5]=[C:6]2[C@@H:7]([CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:2]([CH3:1])[CH2:3]1)=[O:19]
Reactant: CN1CC(C(=O)O)=C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: O
Product: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
130 g of paspalic acid are added rapidly to 780.1 g of a 40% strength solution of tetrabutylammonium hydroxide in water, with stirring and under a stream of nitrogen. The mixture is brought to 30±2° C. and allowed to react at this temperature for 20 hours. The reaction medium is cooled to about 20° C. and held at this temperature for 3 h 30 min. 918 g of water are added, followed by acidification using 95% strength sulphuric acid until the pH is 3.5, while maintaining the temperature at about 30° C. The reaction mixture is then cooled to 10±2° C. and held at this temperature for 30 minutes. The mixture is filtered through a sinter funnel under a vacuum of 0.4 bar, washed 3 times with 300 ml of water and then dried for 14 hours at 75±2° C. and 20 mbar. This gives 107 g of lysergic acid comprising less than 3% of isolysergic acid and the RRi is 80% (RRi=weight of 100% lysergic acid isolated/weight of 100% paspalic employed).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[C:9]1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-benzyl-3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (2.59 g, 6.35 mmol) in dry THF (15 mL) was added a solution of NaOH (3.9 g, 98 mmol) in H2O (15 mL). The reaction mixture was stirred overnight at 80° C. An additional portion of NaOH (4.25 g, 106 mmol) was added and the reaction mixture was stirred at 100° C. during 7 h. The organic solvent was evaporated and the residue was acidified with aqueous 5 M HCl (55 mL). The product was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine (3×20 mL) and dried (Na2SO4). The remaining oil was triturated with heptane (20 mL). The off-white solids were filtered off to give 1.29 g (51%) ACI-06.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[C:13]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30]C)=[O:29]>O1CCCC1.O>[O:4]=[C:5]1[C:13]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (1.48 g, 35.2 mmol) was added to a solution of methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate (6.00 g, 14.2 mmol) in a mixed solvent (tetrahyrofuran/water=2/1 v/v, 180 mL), and stirred at ambient temperature for 16 h. Most of tetrahydrofuran was removed under vacuum, and 150 mL water was added. The solution was extracted with 50 mL of mixed solvent (ethyl acetate/hexanes: 1/3 v/v). The water layer was acidified with 1 N HCl solution until pH 2. After filtration and air dry, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid was obtained (5.60 g, 96%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ13.2 (br s, 1H), 7.95 (dd, J=7.7, 1.2 Hz, 1H), 7.51 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.24-7.14 (m, 2H), 7.12-6.96 (m, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.58 (s, 1H), 6.40 (s, 1H), 5.39-5.18 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.74 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.95 (s, 3H), 2.95 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 168.7, 161.6, 161.2, 143.0, 137.6, 133.0, 132.6, 131.5, 129.8, 129.2, 127.7, 126.4, 124.2, 123.6, 120.9, 120.4, 119.7, 109.7, 92.9, 80.5, 72.6, 57.5, 42.5, 28.8; MS (ES+) m/z 414.0 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]1=[O:25])=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)C.O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]1=[O:25]
Reactant: CC(C)(C)OC(=O)NCCCCCCn1c(=O)ccc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[6-(N-tert-Butoxycarbonylamino)-1-hexyl]-1,2-dihydroquinoline-2-one (480 mg) was treated with a large excess of hydrogen chloride in dietyl ether with stirring for 1 hour at room temperature. The crystalline product was isolated by filtration and redissolved in water whereafter the solution was made strongly alkaline with sodium hydroxide and extracted twice with chloroform. The organic phase was dried over potassium carbonate, filtered and evaporated to yield the title compound as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (3.50 g, 0.0165 mol), (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (4.12 g, 0.0206 mol) and methanol (100.0 mL, 2.469 mol). The mixture was heated at reflux for 2 hours. The mixture was allowed to cool and the volatiles were removed under reduced pressure. The crude oil was chromatographed using a methylene chloride:methanol (0-10%) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])C>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(F)cc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(CCc2ccc(F)cc2)c[nH]1
Yield: 84.5 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 22.14 mmol) was added to a stirring, room temperature solution of 72 (1.1571 g, 4.428 mmol) in MeOH (11.1 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (10 min). Upon cooling, the reaction solidified. The product was concentrated and then dissolved in H2O. The product was extracted with EtOAc, then the aqueous layer was made acidic (pH=2) with the dropwise addition of 10% aq. HCl. The product oiled out of solution, so EtOAc was added, and the organic layer was removed, dried with Na2SO4, filter, concentrated to obtain 73 (0.8724 g, 84.4%) as an off-white solid. The product was further purified by repeating the above procedure. The product was dissolved in 10% NaOH, washed with EtOAc, and then acidified with 10% HCl. As before, the product oiled out and was therefore extracted into EtOAc, dried with Na2SO4, filtered, and concentrated. 1H (CD3OD, 400 MHz): δ 7.14 (2H, dd, J=8.8, 5.4 Hz), 6.94 (2H, t, J=8.8 Hz), 6.68 (1H, d, J=1.7 Hz), 6.66 (1H, d, J=7.1 Hz), 2.82 (2H, t, J=7.3 Hz), 2.72 (2H, t, J=7.3 Hz) ppm. 13C (CD3OD, 100 MHz): δ 164.48, 162.69 (d, J=241 Hz), 139.28 (d, J=3.2 Hz), 131.08 (d, J=8.2 Hz), 126.08, 123.47, 122.68, 116.41, 115.68 (d, J=21.0 Hz), 37.77, 29.94 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 37.77, 29.94; CH carbons: 131.08 (d, J=8.2 Hz), 122.68, 116.41, 115.68 (d, J=21.0 Hz) ppm. HPLC: 9.575 min.