Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(OCC)C>C(O)C>[C:14]([CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 5.5 h

Procedure:
Combine t-butyl 1-piperazinecarboxylate (10.47 g, 56.2 mmol), ethyl acrylate (8 mL) in ethanol (30 mL). Heat at reflux. After 5.5 hours, cool the reaction mixture and evaporate in vacuo to give a residue. Combine the residue and diethyl ether (200 mL) and extract with a 1M aqueous solution of hydrochloric acid. Adjust the pH of the aqueous layer to basic using sodium bicarbonate and then extract with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give t-butyl 4-carboethoxyethyl-1-piperazinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=O)/[C:7](=[CH:23]\O)/[CH2:6]2)=[O:4].Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:34]=[CH:23][C:7]=1[CH2:6]2)=[O:4]
Reactant: NNc1ccc(F)cc1
Reactant: COC(=O)[C@]12C/C(=C/O)C(=O)C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A mixture of (R)-7-[1-hydroxymeth-(Z)-ylidene]-6-oxo-4,6,7,8-tetrahydro-3H-isoquinoline-2,8a-dicarboxylic acid 2-tert-butyl ester 8a-methyl ester (3.8 g), 4-fluorophenylhydrazine hydrochloride (2.7 g), sodium acetate (1.4 g) and acetic acid (30 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was partitioned between diethyl ether and 2.0 M aqueous hydrochloric acid solution. The organic phase was washed with water, aqueous potassium carbonate solution and brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with a mixture of cyclohexane and diethyl ether to afford the title compound as a yellow solid (3.7 g). 1H NMR (CDCl3): δ 7.48-7.39 (m, 3H), 7.21-7.12 (m, 2H), 6.45-6.41 (s, 1H), 4.69-4.55 (d, 1H, J=13 Hz), 4.32-3.98 (m, 1H), 3.64 (s, 3H), 3.51-3.33 (m, 1H), 3.00-2.71 (m, 3H), 2.59-2.51 (d, 1H, J=16 Hz), 2.48-2.34 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([C:41]([OH:43])=[O:42])([F:45])[F:44]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Yield: 50 %

Procedure:
Condensation of BocDTrpOPFP (2.35 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 1.49 g.) by the activated ester method gave BocDTrp-Leu-MetNH2 in 71% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MetNH2 (1.75 g.) using trifluoroacetic acid gave HDTrp-Leu-MetNH2 trifluoroacetate salt in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:20]([O:25][C:26](=[O:31])[C:27]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Product: CCCCCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
The above compound was prepared from 3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid amylester using a procedure analogous to that of Example 102.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][CH3:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (commercially available) 4-(2-hydroxymethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and (1 eq) MeI dissolved in THF was treated with NaH (2 eq) and stirred at RT for 2 h. After work-up, the crude solid was purified by SiO2 chromatography (Ethyl acetate-Heptane 1:4) to give the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCCNC4=O)cc1F

Procedure:
The title compound, off-white solid (66 mg, 76%), MS (ISP) m/z=348.6 [(M+H)+], mp 265° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])#[N:2].S(=O)(=O)(O)[OH:28]>>[NH2:2][C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])=[O:28]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)CCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Product: COC(=O)CCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-[({[4-cyano-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]propanoate (36.0 g) was added portion wise to concentrated sulfuric acid (150.0 mL) at ambient temperature over 20 min. The resulting suspension was heated to 45° C. over 90 min. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into ice water (600 ml), stirred for 30 min. The solid which formed was collected by filtration and washed with water then dried in vacuo to give the title compound as an off white solid (28.0 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][C@@H:5]([C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][C:13]=2[F:24])=[O:10])[CH2:4]1.[O:25]=[C:26]1[NH:31][C:30]2[N:32]=[C:33]([CH:36]=O)[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:11][C:9]([C@H:5]1[CH2:4][C@H:3]([CH2:2][NH:1][CH2:36][C:33]3[CH:34]=[CH:35][C:29]4[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=4[N:32]=3)[C@H:7]([OH:8])[CH2:6]1)=[O:10])=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: COc1ccc2ncc(F)c(NC(=O)[C@H]3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(NC(=O)[C@H]3C[C@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 18.1 %

Procedure:
To a stirred solution of (±)-(1S,3R,4R)-3-(aminomethyl)-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide (0.43 g, 1.29 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.25 g, 1.29 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.41 g, 1.93 mmole). After 4 h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.12 g, 18%) as light yellow solid: 1H NMR (400 MHz, d8-dioxane), δ8.75 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.35 (m, 1H), 4.10 (s, 3H), 3.78 (s, 2H), 3.49 (s, 2H), 3.36 (m, 1H), 2.81 (m, 1H), 2.73 (m, 1H), 2.20 (m, 3H), 2.04 (m, 1H), 1.87 (m, 1H). LC-MS (ES) m/e 513 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:17]1([NH:16][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]3[C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCC1
Reactant: Nc1c2c(nn1-c1ccccc1)CCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-n2nc3c(c2NC2CCCCC2)CCCC3)cc1

Procedure:
In analogy to the procedure described in example 1.1, a mixture of 2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-ylamine (Andrew, Herbert F.; Buckley, Donald. (1963), GB 926327) and cyclohexanone ([108-94-1]) was reacted with sodium triacetoxyborohydride in the presence of acetic acid in CH2Cl2 under reflux conditions for 5 h to give the title compound as colorless oil. MS: m/e=296.4 [M+H+].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:32]1([CH2:38][C:39]([N:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=3)[CH2:4]2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(C(=O)Cc3ccccc3)C2)cn1
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a stirred suspension of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (348 mg) and phenylacetyl chloride (139 mg) in dichloromethane (1 mL) in an ice bath and the resulting mixture was stirred at the same temperature for three hours. The mixture was extracted with chloroform and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate to afford ethyl (2E)-3-(5-{[(3R)-1-(phenylacetyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (225 mg) as a pale brown viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:14]([O:16]C)=O)[C:3]=1[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45]>C1COCC1.C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6](=[O:8])[N:45]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:14]2=[O:16]
Reactant: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(CCN(C)C)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a solution of 4-amino-2-(methoxycarbonyl)-3-methyl-5-nitrobenzoic acid (0.43 g, 1.69 mmol), EDCI hydrochloride (0.36 g, 1.86 mmol), and HOBt (0.23 g, 1.69 mmol) in 22 mL of anhydrous THF was added 1.18 mL of triethylamine and stirred for 10 min at rt under an argon atmosphere. N1,N1-dimethylethane-1,2-diamine (0.16 g, 1.86 mmol) was added into above mixture and the reaction mixture was heated at reflux for 14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.44 g (90%) of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, ArH), 8.12 (br s, 2H, NH2), 3.64 (t, J=6.5 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 2.45 (t, J=6.5 Hz, 2H, CH2), 2.15 (S, 6H, 2×CH3); Mass (ESI, positive) m/z 293.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:3]1[C:2]([Cl:1])=[N:6][N:5]([CH3:7])[C:4]1=[O:8]
Reactant: Cc1ccccc1-n1c(Cl)nn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(Cl)n(-c2ccccc2CBr)c1=O

Procedure:
Preparation of ##STR16## a) 8.95 g of 5-chloro-2-methyl-4-(o-tolyl)-2,4-dihydro[1,2,4]triazol-3-one (prepared according to WO 95/14009) and 7.83 g of N-bromosuccinimide are placed in 50 ml of carbon tetrachloride, and a catalytic amount of dibenzoyl peroxide is added. The suspension is then stirred under reflux with illumination (a 500 W photographic lamp) for 11/2 hours. The suspension is concentrated by evaporation and the residue is chromatographed directly on silica gel using hexane/ethyl acetate (6:4). Recrystallization from toluene/heptane (1:1) gives 4-(2-bromomethylphenyl)-5-chloro-2-methyl-2,4-dihydro[1,2,4]triazol-3-one as white crystals of m.p. 131.5-133° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6](Cl)=[O:7])[CH2:3][CH2:2]1.[CH:9]([C:12]1[C:13]([NH2:21])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:4][CH2:5][C:6]([NH:21][C:13]2[C:12]([CH:9]([CH3:11])[CH3:10])=[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1c(NC(=O)CCC2CC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product from Example 114D (100 mg, 0.754 mmol) in CH2Cl2 (0.5 mL) was added to a stirring solution of the product from Example 112C (109 mg, 0.62 mmol) in pyridine (1.0 mL) at room temperature. The solution was stirred at room temperature for 2 hours, and then quenched by addition of methanol (0.5 mL). After 30 minutes, the solution was concentrated under vacuum, and the residue was purified by flash chromatography (silica gel, eluted with EtOAc), followed by crystallization from 80% EtOH-water to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 0.07-0.18 (m, 2H) 0.40-0.53 (m, 2H) 0.71-0.89 (m, 1H) 1.41 (d, J=7.1 Hz, 6H) 1.63 (q, J=7.2 Hz, 2H) 2.55 (t, J=7.5 Hz, 2H) 3.14 (hept, J=7.1 Hz, 1H) 6.91 (dd, J=7.0, 4.2 Hz, 1H) 8.42 (dd, J=4.1, 1.7 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H) MS (ESI) m/z 273 (M+H)+; Anal. Calculated for C15H20N4O: C, 66.15; H, 7.40; N, 20.57. Found: C, 66.39; H, 7.28; N, 20.26.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[N:6][CH:7]=1.C[Sn](C)(C)[C:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH:20]=1.C(OCC)(=O)C.[F-].[K+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:23]1[C:22]2([CH2:27][CH2:28][C:19]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]4=[O:16])=[N:6][CH:7]=3)=[CH:20][CH2:21]2)[O:26][CH2:25][CH2:24]1
Reactant: C[Sn](C)(C)C1=CCC2(CC1)OCCO2
Reactant: COCC1CN(c2ccc(Br)cn2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)cn2)C(=O)O1
Reaction time: 18 h
Yield: 37.5 %

Procedure:
A suspension of 1.4 g of 3-(5-bromo-pyridin-2-yl)-5-methoxymethyl-oxazolidin-2-one, 1.4 g of 8-trimethylstannyl-1,4-dioxa-spiro[4,5]dec-7-ene and 0.3 of bis(triphenylphosphine)palladium(II) dichloride in 20 ml of tetrahydrofuran was stirred at 70° under argon for 18 h. Then, the mixture was cooled, treated with 150 ml of ethyl acetate and 150 ml of saturated potassium fluoride solution and stirred for 30 minutes. The mixture was filtered over a Celite® pad, the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, concentrated and chromatographed over silica gel 60 with diethyl ether as the eluent. There was obtained 0.6 g of (RS)-3-[5-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one. 1H-nmr(CDCl3) ppm: 8.41 (s, 1H), 8.03 (d, 1H), 7.89 (d, 1H), 6.08 (t, 1H), 4.82 (m, 1H), 4.21 (t, 1H), 3.91 (t, 1H), 3.92 (s, 4H), 3.60 (m, 2H), 3.32 (s, 3H), 2.54 (m, 2H), 2.38 (m, 2H), 1.82 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@:9]([CH2:14][CH:15]([CH2:17][OH:18])[OH:16])([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:19])[CH3:2].C(=O)([O-])O.[Na+].[CH2:25](Br)[C:26]1C=CC=[CH:28][CH:27]=1>CS(C)=O>[CH2:1]([O:3][C:4]1[C@@:9]([CH2:14][CH:15]([CH2:17][OH:18])[OH:16])([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[O:19][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC1=C(OCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 25.4 %

Procedure:
Under an argon atmosphere, 3-O-ethylglyceryl ascorbic acid (3.03 g) obtained in Example 7 was stirred in DMSO (10 mL), and further, sodium hydrogen carbonate (0.92 g) and benzyl bromide (1.79 g) were added. The mixture was heated up to 100° C. and stirred for 5 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 2.16 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.3), and concentration was performed under reduced pressure to obtain 3-O-ethylglyceryl-2-O-butyl ascorbic acid (0.89 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:8][N:7]=1)=[O:5])[CH3:2].[O-][Cl:15].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:15])=[C:9]([CH2:11][CH2:12][CH3:13])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: [O-]Cl
Reactant: CCCc1cc(C(=O)OCC)n[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1[nH]nc(C(=O)OCC)c1Cl

Procedure:
Following protocol K, 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester was treated with glacial acetic acid and NaOCl under similar reaction conditions, yieliding the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (24.61 g, 96 mmol) was dissolved in acetic acid (100 ml) and the mixture was cooled to 10° C. Nitric acid fuming (Fluka ID 84392, 100%, 10 ml, 240 mmol) was added dropwise to the cooled solution over 2 hours. The reaction mixture was allowed to come to room temperature and stirred for 16 hours. The reaction mixture was poured into water (400 ml). The precipitate was filtered, washed with water, then taken up in sodium hydrogencarbonate saturated aqueous solution (300 ml) and stirred for 2 hours. The precipitate was filtered, washed with water and dried. The raw product was recrystallized from ethyl alcohol (1000 ml) to give 18.25 g of product [B]. Yield 65%.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11]1.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][CH:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[CH:11]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1cn(C)c2ccccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropyl amide, LDA, (5.5 millimole) in 10 mL of dry tetrahydrofuran at -78° C. was added dropwise a solution of methyl 2-(1-methyl-3-indolyl)acetate (1.02 g) in 3 mL of dry tetrahydrofuran. This mixture was stirred for one hour, then 1.42 g of methyl iodide was added and the mixture was warmed to room temperature and stirred for an additional 30 minutes. The mixture was poured into a solution of aqueous saturated ammonium chloride and then extracted with diethyl ether. The ether extract was dried over magnesium sulfate and concentrated to an oil by evaporation. The residue was subjected to silica gel chromatography using a developing solution of hexanes/ethyl acetate (6:1 by volume) to give 1.04 g of the product.