Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:32])([F:33])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To the solution of 1H-1,2,4-triazole (0.06 g) in DMF was added sodium hydride (0.04 g) while cooling with ice, and the mixture was warmed to room temperature and then stirred for 0.5 hr. To this solution was added the solution of 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]2-fluorobenzonitrile (0.30 g) in DMF, and the mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.18 g). 1H-NMR (DMSO-d6) δ: 2.62-2.73 (1H, m), 2.95-3.03 (1H, m), 3.49-3.55 (2H, m), 3.90 (1H, d), 4.31 (1H, d), 7.09 (1H, dd), 7.29 (1H, d), 7.61 (1H, d), 7.68 (2H, d), 7.71 (1H, t), 8.26 (1H, s), 8.98 (1H, s)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.Cl[CH2:24][CH:25]=O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]2[S:21][CH:24]=[CH:25][N:22]=2)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2ccccc2)cnc1NC(N)=S
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccccc2)cnc1Nc1nccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
[3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea (0.24 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred 3 hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine (“A20”) is obtained after reversed phase chromatography (water/acetonitrile 0.1% TFA) as yellow solid in a yield of 45%; mp. 140.6-140.9°; HPLC (method C): 1.73 min; LC-MS (method A): 1.589 min, 344.1 (M+H+);
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:18][Si:19]([C:22]#[C:23][CH2:24][OH:25])([CH3:21])[CH3:20]>C([O-])(O)=O.[Na+]>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][CH2:24][O:25][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C[Si](C)(C)C#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C[Si](C)(C)C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask was charged with dihydropyran, (3.5 mL, 39 mmol) and pTSA, (7 mg, 0.039 mmol) was added. When the pTSA had dissolved, the solution was cooled to 0° C. in an ice bath and 3-(trimethylsilyl)propargyl alcohol, (5.7 mL, 39 mmol) was added dropwise. It was allowed then allowed to warm slowly to room temperature and held for 1 h. The mixture was added to saturated NaHCO3, (250 mL) extracted with Et2O, (150 mL) (×3), washed with brine, (150 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography eluting with heptane-EtOAc, gradient 0 to 10% EtOAc. 8.5 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.19 (s, 9H) 0.77-0.94 (m, 1H) 1.49-1.59 (m, 1H) 1.57-1.70 (m, 2H) 1.69-1.93 (m, 2H) 3.35-3.63 (m, 1H) 3.78-3.91 (m, 1H) 4.19-4.35 (m, 2H) 4.82 (t, J=3.34 Hz, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].C(O)(=O)C>O>[OH:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Acetic anhydride (79.6 g, 0.76 mol, 1.46 equiv) was added over 1.5 hours to the mixture of 2-amino-5-nitrophenol (80 g, 0.52 mol, 1.00 equiv) and acetic acid (320 ml, 5.2 mol, 10 equiv) at 60° C. After 1 hour, additional acetic anhydride was added (7.4 g, 0.071 mol, 0.137 equiv). After another 1 hour, the mixture was cooled and diluted with 200 ml of water. Solid was formed and collected by filtration and washed with water and heptane. The solid was dried in a vacuum oven to give the title compound 94 g. MS (ESI) m/z: 197 (M+1).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]=2[CH2:2]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>CO.O>[N:8]1[C:3]2[CH2:2][CH2:1][CH2:11][C:9](=[N:13][OH:14])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ncccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1CCCc2ncccc21
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 5,6,7,8-tetrahydroquinolinone-5 (93) (Tyger Scientific, Ti 1850), 3.0 eq of hydroxylamine hydrochloride (Aldrich, 37,992-1), and 3.0 eq of sodium acetate in 50 mL of MeOH and 15 mL of H2O was refluxed for 4 hrs. The mixture was allowed to cool to rt. After rotary evaporation of the MeOH, 100 mL of H2O was added. The solid formed was collected by vacuum filtration. The solid collected was triturated with hexanes and dried under vacuum to give 94.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CCCCCCC>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1
Reactant: COc1cc2ncc(NC3CC4CCC3C4)nc2cc1OC
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCCC
Product: COc1cc2ncc(N[C@@H]3C[C@H]4CC[C@@H]3C4)nc2cc1OC

Procedure:
The (±)-bicyclo[2.2.1]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine of Example 17 is resolved on a chiral HPLC column (Chiralpac AD, 25×2 cm, 60% heptane/40% ethanol with 10 mM (1S)-(+)-camphorsulfonic acid, 12 mL/minute) and the above titled product is obtained as the first eluent. The fractions collected are combined and washed with 50 mL of 1 N NaOH before drying (MgSO4). The solution after filtration is concentrated on a rotovap and then dried under a high vacuum. A yellow solid is obtained. [α]d20+19.5° (c=0.20, CH2Cl2) m.p. 184-186° C. Anal. calcd for C17H21N3O2×0.3 H2O: C, 66.90; H, 7.15; N, 13.77. Found: C, 66.86; H, 7.01; N, 13.86.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:15][CH:17]1[O:19][CH2:18]1)(=[O:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CO1
Reaction time: 96 h

Procedure:
0.376 mol (73.7 g) of 2-acetylamino-5-nitrophenol is dissolved in 375 ml of 1.1 N sodium hydroxide solution, and 300 ml of epichlorohydrin are then added. The reaction medium is left to stand for 96 hours at 20° C., with thorough stirring, and the expected product which has precipitated is then filtered off and washed with water. After recrystallisation from ethanol and drying in vacuo, it melts at 164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C[Si](C)(C)Cl.[C:20](=[O:23])(O)[O-].[Na+].[CH3:25]N(C)C>C(O)CO>[Cl:1][C:2]1[CH:11]=[C:6]([CH:7]2[O:8][CH2:25][CH2:10][O:9]2)[C:5]([OH:12])=[C:4]([CH:3]=1)[C:13]([O:23][CH3:20])=[O:14]
Reactant: COC(=O)c1cc(Cl)cc(C=O)c1O
Reactant: O=C([O-])O
Reactant: CN(C)C
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: OCCO
Product: COC(=O)c1cc(Cl)cc(C2OCCO2)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-chloro-3-formyl-2-hydroxybenzoate (73.2 g), ethylene glycol (350 ml) and trimethylchlorosilane (129 ml) is stirred at room temperature for 2 hours. The reaction mixture is poured into a mixture of an aqueous saturated sodium bicarbonate solution and trimethylamine, and the mixture is extracted with ethyl acetate. The extracted is washed with water, dried and concentrated to remove solvent, whereby methyl 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate (86 g) is obtained as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: CN(C)c1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)ccnc3[nH]2)cc1
Yield: 33.3 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-(dimethylamino)benzaldehyde (31.6 mg, 0.212 mmol) were reacted to produce 25 mg (33%) of the title compound. mp: 245-251° C., 1H NMR (300 MHz, DMSO-d6): 12.73 (s, 1H), 7.96 (d, J=8 Hz, 2H), 7.84 (d, J=4 Hz, 1H), 7.65 (s, 1H), 7.15 (s, 1H), 6.81 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 6.32 (s, 2H), 3.89 (br s, 1H), 2.99 (s, 6H), 2.87 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=7 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 389 (M+H), HPLC: 1.97 min (G method).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH:28]=[CH:29][C:30]([OH:32])=[O:31])=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:8]=2)[CH3:2].[ClH:33].[H][H]>[Pd]>[ClH:33].[CH2:1]([O:3][C:4]1[C:5]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:8]=2)[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(C=CC(=O)O)c(OCC)cc2c1Nc1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)c1cnc2nc(CCC(=O)O)c(OCC)cc2c1Nc1ccc(OC)cc1

Procedure:
A mixture of 3-[3-ethoxy-6-ethoxycarbonyl-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]acrylic acid (2.3 g) , 10% palladium on charcoal (0.5 g), IMS (250 ml) and concentrated hydrochloric acid (0.4 ml) was shaken under an atmosphere of hydrogen until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated with hot ethyl acetate and hot filtered to give 3-[3-ethoxy-6-ethoxycarbonyl-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]propionic acid hydrochloride, m.p. 213°-216° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][CH:29]=[N:28][C:27]=1[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1ccccc1F
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncsc3-c3ccccc3F)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(2-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]#[N:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:25]=[N:26][NH:27][N:24]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N2C(C#N)CCC2c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nn[nH]n2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 92.8 %

Procedure:
To a stirred solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile (0.70 g, 2.03 mmol) in DMF (25 ml) was added at room temperature sodium azide (0.40 g, 6.10 mmol) and triethylamine hydrochloride (0.42 g, 3.05 mmol) and the reaction mixture was stirred at 120° C. for 6 h. The mixture was poured in water (100 ml), acidified (2 N HCl) and the formed solid was collected to give (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole (0.73 g, yield 93%) as an off-white solid, m.p. 150° C.
Reaction SMILES: [CH2:1]([N:5]=[C:6]1[S:10][CH:9]=[N:8][C:7]1([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.O1CCCC1.O>[CH2:1]([N:5]=[C:6]1[S:10][CH:9]=[N:8][C:7]1([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:25][N:26]=[N:27][N:28]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C1SC=NC1(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCN=C1SC=NC1(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)OCC
Yield: 30 %

Procedure:
5-Butylimino-4,5-dihydro-4-ethoxycarbonyl-4-[[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thiazole, the compound resulting from Example 2A (B), (170 mg, 0.241 mmol) in 15:15:1 (v/v/v) acetic acid/tetrahydrofuran/water (4 mL) was heated at reflux for 90 minutes. The solvent was evaporated under reduced pressure, and toluene was added and evaporated. Chromatography of the residue on silica gel eluting with 2-6% methanol in chloroform afforded 33.6 mg (30%) of the desired product as a yellow foam solid. TLC (10% methanol/90% chloroform) Rf =0.33. 1H NMR (CDCl3, 300 MHz) d 0.88 (t, 3H), 1.23 (t, 3H), 1.10-1.65 (envelope, 4H), 3.61 (d, 1H), 3.75 (dt, 2H), 3.81 (d, 1H), 4.08-4.32 (m, 2H), 7.08 (d, 2H), 7.27 (d, 2H), 7.38 (dd, 1 H), 7.50-7.63 (m, 2H), 7.75 (s, 1H), 8.20 (dd, 1H). MS (DCl/NH3) m/e 463 (M+H)+. Anal calcd for C24H26N6O2S.0.25 H2O: C, 61.72; H, 5.72; N, 17.99. Found: C, 61.89; H, 5.32; N, 17.76.
Reaction SMILES: CC1OC(C)=CC=1.[OH:8][CH2:9][C:10]1[O:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>>[OH:15][CH2:14][C:13]1[O:16][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(CO)o1
Agent: Cc1ccc(C)o1
Product: OCc1ccc(CO)o1

Procedure:
In another aspect, the present disclosure provides a method for preparing 2,5-dimethylfuran, which includes the steps of: a) combining 5-(hydroxymethyl)furfural (HMF) with H2, a first catalyst, and an aprotic solvent; b) reacting the mixture of step (a) to form 2,5-bis(hydroxymethyl)furan (BHMF); c) adding a carboxylic acid, and a second catalyst to the reaction mixture of step (b) to form an ester of BHMF; and d) adding H2 to the reaction mixture that includes the ester of BHMF of step (c) to form 2,5-dimethylfuran.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=1>>[Cl:51][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][CH:48]=1)[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(OCCCCBr)c1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4cccc(Cl)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.065 g of 1-(4-bromobutoxy)-3-chlorobenzene are used to prepare the title compound. Rf=029 (2:1 EtOAc-heptane); Rt=6.16.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([OH:29])=O)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH2:44])[CH3:40].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH:44][C:27](=[O:29])[C@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:17][C:15](=[O:16])[C@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:40]
Reactant: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
To a stirred mixture consisting of 4.82 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosine, 1.519 g. of N-hydroxysuccinimide, 1.675 g. of glycine ethyl ester hydrochloride, and 60 ml. of N,N-dimethylformamide, cooled to -15° C., is added first 1.68 ml. of triethylamine and then 2.48 g. of dicyclohexylcarbodiimide, and the resulting mixture is stirred at -15° C. for 2 hours and at room temperature for 25 hours. The mixture is then concentrated to remove solvent, and the residue is partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer is separated, washed with saturated aqueous sodium chloride, with saturated aqueous sodium bicarbonate, and with saturated aqueous sodium chloride again, dried, and evaporated to give a solid residue of N-benzyloxycarbonyl-L-seryl-L-tyrosylglycine ethyl ester; m.p. 166°-169° C., following crystallization from ethyl acetate; [α]D25 -23.2° (2% in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][N:10]=[C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:8]=1.[S:38](N)(N)(=[O:40])=[O:39].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:7]2[N:8]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=4)[N:16]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:15]=3)[N:10]=[CH:11][C:12]=2[NH:13][S:38]1(=[O:40])=[O:39]
Reactant: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)ncc2N)c(OC)c1
Reactant: NS(N)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3NS2(=O)=O)c(OC)c1
Temperature: 160 °C

Procedure:
550 mg (1.093 mmol) of the compound from example 92A were divided between 11 microwave vessels. 50 mg of the substance in each were admixed with 48 mg (0.496 mmol) of sulfamide and 2.5 ml of pyridine and then heated at 160° C. under microwave radiation for 30 min. Subsequently, all batches were combined and freed of the solvent under reduced pressure. The residue was taken up in dichloromethane and extracted three times with water. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 0.130 g (12% of theory, purity 50%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:37]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([N:18]2[C@@H:30]3[C@@H:21]([C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=43)[CH2:20][CH2:19]2)=[O:17])=[O:8])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: O=C(CCCCCBr)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CCCCCN1CCOCC1)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 91.3 %

Procedure:
6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)hexaneamide (166 mg, 0.30 mmol), morpholine (28 μl, 0.331 mmol) and potassium carbonate (207 mg, 1.5 mmol) were heated under reflux for 6 hrs. in acetonitrile (3 ml). Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography and eluted with ethyl acetate to give the title compound (153 mg, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C[N:19]([CH3:22])C=O>ClCCl>[CH2:22]([NH:19][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-fluoro-5-nitrobenzoic acid (313 mg) in dichloromethane (4 mL) were added thionyl chloride (0.17 mL) and dimethylformamide (0.05 mL), and the mixture was heated for 36 hours under reflux. After evaporation of the solvent, the residue was dissolved in dichloromethane (4 mL). To this solution were added benzylamine (0.19 mL) and triethylamine (0.47 mL), and the mixture was stirred for 30 minutes at 0° C. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed successively with diluted hydrochloric acid, an aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with diisopropyl ether to give N-benzyl-2-fluoro-5-nitrobenzamide (436 mg) as a solid substance.