Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:12]=[C:13]=[O:14])[CH3:11].[Si:15]([O:22][C:23]1[CH:28]=[C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:26]=[CH:25][C:24]=1[C@H:37]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClC(Cl)C>[CH2:10]([NH:12][C:13](=[O:14])[O:43][C@H:40]1[CH2:39][CH2:38][C@H:37]([C:24]2[CH:25]=[CH:26][C:27]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31])=[CH:28][C:23]=2[O:22][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[CH2:42][CH2:41]1)[CH3:11]
Reactant: CCN=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)O[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 40 °C

Procedure:
N,N-Diisopropylethylamine (199 μl) and ethyl isocyanate (90 μl) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated to 40° C. for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a solid (55 mg, 95%); Rf (ethyl acetate/petrol, 1:2 v/v) 0.65.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].CS(O)(=O)=O.[OH:10][C@@H:11]1[CH2:16][O:15][C:13](=[O:14])[CH2:12]1>O>[OH:10][C@H:11]([CH2:12][C:13](=[O:14])[O-:15])[CH2:16][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C1C[C@H](O)CO1
Reactant: CN(C)C
Agent: CS(=O)(=O)O
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an aqueous solution of trimethylamine (250 mL), 25% by weight solution of trimethylamine in water, is added (S)-3-hydroxybutyrolactone methane sulfonate (98 g, 0.5 mol) prepared as described above. The resulting solution is stirred at room temperature 1 hr, and then heated at 100° C. in a sealed vessel for 16 hrs. Upon cooling the solution to room temperature, the reaction mixture is evaporated to dryness in vacuo using ethanol and toluene (5:1) to remove residual water by azeotropic distillation. The crude L-carnitine is triturated with anhydrous acetone (100 ml) and the purified L-carnitine thus produced is collected by filtration. [α]D22 -31° (c 10.0, H2O).
Reaction SMILES: [CH2:1]([C@@H:5]1[C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH2:1]([C@:5]1([CH3:16])[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCCC[C@H]1OC(=O)[C@@H]1CCCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCC[C@@H]1OC(=O)[C@]1(C)CCCC
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A solution of β-lactone 3a (36.3 mg, 0.1835 mmol) in 1.9 mL THF was cooled to −78° C. and 370 μL of LiHMDS (0.367 mmol, 2.0 equiv, 1.0 M solution in THF) was added under a nitrogen atmosphere. After 1.5 h, 23 μL (0.367 mmol, 2.0 equiv) of iodomethane was added and the reaction warmed to −40° C. and stirred for an additional 45 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (0→15% Et2O: hexanes) to give β-lactone 8a (28.4 mg, 73%) as a colorless oil and as a mixture of cis/trans diastereomers (dr, 6:1). Data provided for major diastereomer: Rf(15% Et2O:hexanes) 0.64; IR (thin film) 1824 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.18 (dd (major diast.), J=6.0, 8.5Hz, 1H), 1.63-1.78 (m, 2H), 1.45-1.53 (m, 2H), 1.39 (s, 3H), 1.24-1.39 (m, 10H), 0.89-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) 14.1, 14.2, 20.0, 22.1, 25.5, 25.6, 26.5, 30.3, 31.7, 35.9, 56.8, 84.5, 175.5; ESI LRMS Calcd. for C13H24O2Li [M+Li]: 219. Found: 219.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@H:14]2[CH2:15][O:16][C@@H:17]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:18][CH2:19]2)=[CH:27][CH:28]=1
Reactant: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(OCc3ccccc3)cc2)CO1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(O)cc2)CO1

Procedure:
cis-N-{3-[5-(4-Benzyloxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide (25 mg, 0.065 mmol) was dissolved in 5 ml of ethanol and hydrogenated in the presence of 0.69 mg of palladium/carbon under 3 bar for 1 h. The reaction mixture was concentrated and directly reacted further. Yield 18 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C:9](/[CH:17]=[CH:18]/[C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:23]=2)=[N:8]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:44]([C:46]1[C:51]([Cl:52])=[CH:50][N:49]=[CH:48][C:47]=1[Cl:53])[CH3:45])(=O)=O>C(#N)C>[Cl:53][C:47]1[CH:48]=[N:49][CH:50]=[C:51]([Cl:52])[C:46]=1[C@H:44]([O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[C:9]2/[CH:17]=[CH:18]/[C:19]1[CH:20]=[N:21][N:22]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:23]=1)[CH3:45]
Reactant: Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1
Reactant: C[C@H](OS(C)(=O)=O)c1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 3-neck 250 mL round bottom flask equipped with an internal temperature probe, reflux condenser, nitrogen blanket and magnetic stir bar, slurry (E)-1-(tetrahydro-2H-pyran-2-yl)-3-(2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazol-5-ol (10.0 g, 22.83 mmol) and cesium carbonate (7.88 g, 23.94 mmol) in ACN (92 mL) and warm to 60° C. To the suspension, add (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (7.03 g, 26.02 mmol) and stir overnight. Cool the reaction mixture to RT, filter and wash solids with ACN. Concentrate the filtrate and purify the residue by silica gel chromatography (2-4% (2 M ammonia in methanol)/DCM). Combine product fractions and concentrate in vacuo to a white foam. Yield: 12.5 g (86%). MS (ES) m/z 612 [M+1]+.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1.[OH-].[K+]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([SH:4])=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cc(SC(=O)N(C)C)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(S)ccc1Br
Temperature: 90 °C
Yield: 84.2 %

Procedure:
A mixture of S-4-bromo-3-methylphenyl dimethylcarbamothioate (4.56 g, 16.6 mmol) and potassium hydroxide (3.27 g, 58.2 mmol) in MeOH was heated at 90° C. for 1 hour. The mixture was cooled to RT and concentrated. The residue was redissolved in DCM and aqueous sodium bicarbonate (sat.) and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (100% hexanes) to afford 2.84 g of 4-bromo-3-methylbenzenethiol as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:12][C:6]1[C:5]([CH2:4][OH:3])=[C:10]([Cl:11])[CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1c(Cl)ccnc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
The required (2,4-dichloro-pyridin-3-yl)-methanol was prepared as follows: To a solution of 2,4-dichloropyridine (3.00 mL; 27.8 mmol) in THF (25 mL) was added dropwise a solution of LDA (15.3 mL; 2.00 mol/l in THF/heptane/ethylbenzene; 30.6 mmol), at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Subsequently, a solution of ethyl chloroformate (3.2 mL; 33.33 mmol) in THF (5 mL), was added dropwise, at −78° C. and the mixture was stirred for another 1 h at the same temperature. To the resulting mixture was added 5% aqueous NaHCO3-solution, dropwise, at −78° C. The mixture was allowed to warm to RT and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3) to afford 2,4-dichloro-nicotinic acid ethyl ester (2.45 g). To a solution of 2,4-dichloro-nicotinic acid ethyl ester (2.35 g; 10.68 mmol) in THF (50 mL) was added dropwise diisobutylaluminum hydride (32.0 mL; 1.00 mol/l in THF, 32.0 mmol), at 4° C. After 15 minutes the ice-bath was removed and the reaction mixture was stirred at RT overnight. Subsequently, the resulting mixture was concentrated in vacuo and partitioned between 5% aqueous NaHCO3 and EtOAc. The layers were separated and the organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Et2O:hexanes 1:1) to afford (2,4-dichloro-pyridin-3-yl)-methanol (0.40 g).
Reaction SMILES: N[C:2]1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[S:30]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1C)(=[O:32])=[O:31]>>[NH2:27][C:25]1[CH:24]=[CH:23][C:22]([S:30]([NH:33][C:34]2[CH:35]=[C:36]([CH3:2])[CH:37]=[CH:38][CH:39]=2)(=[O:31])=[O:32])=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1C
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: COc1cc(N)ccc1S(=O)(=O)Nc1cccc(C)c1

Procedure:
(RK1-1-39) I This compound was prepared according to the procedure described for compound 12a except using 11h to obtain the required product as an orange-brown solid in (169 mg, 66%). Mp: not determined; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 1H), 6.99 (t, J=7.8 Hz, 1H), 6.82 (br s, 1H), 6.79-6.73 (m, 2H), 6.65 (br s, 1H), 6.11 (d, J=2.0 Hz, 1H), 6.09 (s, 1H), 3.99 (br s, 2H), 3.86 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=[CH:21]1>C1(C)C=CC=CC=1.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]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:23]1[N:22]=[CH:21][N:20]([CH3:19])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc3nc(Cl)ccc3n2Cc2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.12 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was heated to 110° C. for 7 hours. Toluene was removed in vacuo and the mixture was dissolved in MeCN and filtered. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded purified product (24 mg, 24%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:25]([C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
A mixture of (4-tert-butoxycarbonylaminopiperidin-1-yl)acetic acid (0.50 g; 1.94 mmol), phenylamine (0.18 mL; 1.94 mmol), the coupling reagent TBTU (0.62 g; 1.94 mmol) and DIPEA (0.35 mL; 2.0 mmol) in DMF (5 mL) is stirred at r.t. over night. The solvent is evaporated and the residue is purified by silica gel column chromatography (DCM:MeOH=40:1) to give tert-butyl N-[1-(2-anilino-2-oxo-ethyl)-4-piperidyl]carbamate.
Reaction SMILES: C[O:2][C:3]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:20]=2[N:21]=1)([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:4].CCO>C(=O)=O>[OH:2][C:3]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:20]=2[N:21]=1)([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:4]
Reactant: COc1cc(C)c2[nH]ccc2c1C(C)(OC)c1nc2cc(C#N)ccc2o1
Agent: O=C=O
Solvent: CCO
Product: COc1cc(C)c2[nH]ccc2c1C(C)(O)c1nc2cc(C#N)ccc2o1

Procedure:
Resolution of the enantiomers of 2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)benzo[d]oxazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 60% EtOH (0.2% DEA) in CO2 to give (+)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)benzo[d]oxazole-5-carbonitrile (tr=6.31 min) and (−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)benzo[d]oxazole-5-carbonitrile (tr=11.01 min).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][OH:27]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH2:26][OH:27])=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: OC[C@H]1CCCN1
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC[C@@H]3CO)nc21

Procedure:
The title compound, m.p. 239°-242° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (R)-(-)-2-pyrrolidinemethanol using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 160°-170° C. for 2 hrs, and the product was crystallized from chloroform/hexane.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH2:8])[CH3:2].[K+].[CH2:31]([S:33]([NH-])(=[O:35])=[O:34])[CH3:32]>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH:8][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH3:2]
Reactant: CCS([NH-])(=O)=O
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNS(=O)(=O)CC
Yield: 19.4 %

Procedure:
A solution of the methanesulfonic acid ester intermediate of Example 48 (25 mg, 53 μmol) and ethanesulfonamide potassium salt (16 mg, 106 μmol) in DMF (2 mL) is stirred at 60° C. for 18 h. The mixture is concentrated and separated by prep. HPLC to give the title compound (5 mg) as a colourless oil; LC-MS: tR=1.14 min, [M+H]+=487.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J26) (300 mg, 0.96 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (383 mg, 0.96 mmol) according to the general procedure M. Obtained as a light yellow oil (530 mg, 86%).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH3:17])[CH:13]=[CH:12][C:11]([S@:14]([CH3:16])=[O:15])=[CH:10][CH:9]=1.[CH2:18]([O:25][C:26]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]=[O:35])=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:25][C:26]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]([OH:35])[CH2:16][S@@:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:17])=[CH:9][CH:10]=1)=[O:15])=[O:31])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1ccc([S@](C)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc([S@@](=O)CC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To diisopropylamine (0.26 ml) in THF (6 ml) was dropwise added 1.62M n-butyllithium-hexane solution (1.12 ml) at -78° C., and the mixture was stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -30° C., dropwise added with (S)-(-)-methyl p-tolyl sulfoxide (255 mg) in THF (6 ml), and stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -78° C. and dropwise added with known N-benzyloxycarbonyl-L-prolyl-L-prolinal (300 mg) in THF (6 ml). After stirring for 0.5 hour, an aqueous solution of saturated ammonium chloride was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine order, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate; chloroform-methanol) to give 388 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[CH:18]=1)[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[C:18]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCc1cc2cc(Cl)ccc2o1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1oc2ccc(Cl)cc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 7.06 g 2-ethyl-5-chlorobenzo[b]furan in the presence of 11.4 g aluminum chloride. Colorless crystals, m.p. 130°-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].[C:13]([N:21]=C=O)(=[O:20])C1C=CC=CC=1.[OH-].[Na+]>O1CCOCC1>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH:10]2[CH2:11][CH2:12]2)[NH:1][C:13](=[O:20])[N:21]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1c(N)cccc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nc(=O)[nH]c2cccc(C3CC3)c12
Temperature: 75 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
A solution of 2-amino-6-cyclopropylbenzonitrile (Example 92a) (1.0 eq., 1.0 mmol, 158 mg) and benzoyl isocyanate (90% pure, 1.0 eq., 1.0 mmol, 1.171 g/mL, 140 μL) in dioxane (15 mL) was stirred at room temperature. After 2 hours, the volatiles were removed on a rotary evaporator. The resulting crude N-benzoyl urea was suspended in EtOH (10 mL, 200 proof) and NaOH (2.5 eq., 2.5 mmol, 1N, 2.50 mL) was added. The reaction was heated to 75° C. with stirring for 7 hours. The solvent were evaporated and the residue diluted with water (10 mL). The reaction mixture was acidified with 10% citric acid/water solution and carefully titrated to pH 7-8 with saturated NaHCO3 solution. The precipitated product was collected by vacuum filtration, washing with water. The residue was suspended in EtOH (3 mL, 200 proof) and HCl was added (12.1N, 3 mL). The mixture was heated to 90° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (20 mL), filtered (0.45 μm PTFE frit), and the filtrate concentrated on a rotary evaporator. The residue was further purified by preparative TLC (1000 μm, 10/90 MeOH/DCM) and trituration with methanol at room temperature. The reaction gives 25 mg (12.4%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.802 (m, 2H), 1.086 (m, 2H), 2.345 (m, 1H), 6.922 (d, J=8 Hz, 1H), 7.000 (d, J=8 Hz, 1H), 7.253 (br. s, 1H), 7.397 (t, J=8 Hz, 1H), 8.022 (br. s, 1H), 10.644 (s, 1H). MS 202 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=O)[C:7]2=[O:16])=[CH:2]1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[N:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=3)[C:7]2=[O:16])=[CH:2]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(c2ccsc2)c2ccccc21
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1c1ccsc1
Temperature: 140 °C
Yield: 18.2 %

Procedure:
A mixture of 1-(3-thienyl)-2H-indole-2,3-dione (25 mg, 0.11 mmol) (prepared as described below) and 3-trifluoromethylaniline (14 uL, 0.11 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate and hexane as the eluent, giving the desired product as a yellow solid (7.3 mg, 0.02 mmol, 22%). 1H NMR (400 MHz) δ 7.62-7.19 (m, 9H), 6.94 (d, J=8.0, 1H), 6.76 (t, J=7.6, 1H); ESI-MS m/z found 373 (MH+).
Reaction SMILES: [OH-:1].[K+].Cl.N([CH2:11][CH2:12][OH:13])(CCO)CCO>>[O:1]=[CH:11][C@@H:12]([C@H:11]([C@@H:12]([C@@H:11]([CH2:12][OH:13])[OH:1])[OH:13])[OH:1])[OH:13]
Reactant: [OH-]
Reactant: OCCN(CCO)CCO
Agent: Cl
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 0 °C

Procedure:
Portions of tissues (200-300 mg) were weighed and homogenized in 500 μl ice-cold 0.5 M perchloric acid using 6 mm ceramic beads on a tissue lyzer. Homogenates were centrifuged (10 min at 10,000), and resultant supernatants were neutralized (pH ˜7.4) with 5 M KOH plus 0.5 M triethanolamine hydrochloride with the help of pH paper and centrifuged (10 min at 10,000 g). Most of the procedures were performed at room temperature unlike suggested in the paper. A portion (200 μl) of the neutralized extract was reconstituted in 1 ml of Optiphase supermix and 200 μl of this radioactive mix was counted on a Microbeta unit to access total radioactivity (2-[3H]DG+2-[3H]DG-6-P). Another aliquot (200 μl) was mixed with 200 μl of 0.3 N Ba(OH)2 and 0.3 N ZnSO4. This mixture was centrifuged, and the supernatant was used to determine unphosphorylated 2-[3H]DG levels by using a portion (200 μl) of the neutralized extract was reconstituted in 1 ml of Optiphase supermix and 200 μl of this radioactive mix was counted on a Microbeta unit. Quench corrections were not made at this time. Tissue 2-[3H]DG-6-P was calculated as the difference between total and 2-[3H]DG values.