Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.C[NH:27]C1C=CC=CC=1>>[NH2:27][CH2:1][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: CNc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=CNCCCCN)cc1

Procedure:
The compound of Example 13 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-methylaniline solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 303.38; found mol. wt. (M+H) 304.2
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH:19]=[C:18]2[O:37][S:39]([CH3:38])(=[O:41])=[O:40])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 50.6 g (98 mmols) of 7β-phenoxyacetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 500 ml of methylene chloride is cooled to -20° C. and, after adding 14 ml of methanesulphonyl chloride (142 mmols), 22.3 ml (142 mmols) of triethylamine are added slowly. After a reaction period of 1 hour at -15° C. to -20° C. under nitrogen, the solution is washed with water, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, concentrated in a rotary evaporator and dried under a high vacuum. A mixture consisting of 7β-phenoxyacetylamino-3-methanesulphonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 7β-phenoxyacetylamino-3-methanesulphonyloxy-2-cephem-4-carboxylic acid diphenylmethyl ester is obtained; thin layer chromatogram (silica gel; toluene/ethyl acetate, 2:1), 3-cephem derivative Rf=0.39; 2-cephem derivative Rf=0.32.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C1C=CC=CC=1)(=O)=O)[CH:7]=[CH:6]2)#[N:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)#[CH:24]>CCCCCCC.CCOC(C)=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]#[C:24][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]3)=[CH:26][CH:27]=1
Reactant: N#Cc1ccc2cc(OS(=O)(=O)c3ccccc3)ccc2c1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2ccc3cc(C#N)ccc3c2)cc1

Procedure:
This product was prepared from benzenesulfonic acid 6-cyano-naphthalen-2-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 95:5; yield (140 mg, 98%); 1H NMR δ (CDCl3): 8.20 (s, 1H), 8.06 (s, 1H), 7.88 (t, J=7.81 Hz, 2H), 7.71-7.59 (dm, 2H), 6.92 (m, 2H), 3.83 (s, 3H); LCMS m/z: 283.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH3:27]>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH3:27]
Reactant: Cc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)ccc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-3-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (256 mg) in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN/IPE to give the title compound (169.3 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][C:5]1(C(OC)=O)[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]>C(O)(=O)C.Cl>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]
Reactant: COC(=O)C1(CCC(C)(C)C)CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)CCC1CCCC1=O
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A solution consisting of 23.0 g (101.7 mmol) of methyl 1-(3,3-dimethylbutyl)-2-oxocyclopentanecarboxylate in 80 ml of acetic acid and 80 ml of conc. hydrochloric acid is stirred at 90° C. for 14 hours. After the reaction has ended, the mixture is cooled to room temperature and ice-water is added. The product is extracted with diethyl ether. The org. phase is washed with water, dried with sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel 60-120, mobile phase: ethyl acetate 3%/petroleum ether). This gives 10 g (59% of theory) of 2-(3,3-dimethylbutyl)cyclopentanone.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6](Cl)(=[O:10])/[CH:7]=[CH:8]/[CH3:9].[CH2:12]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]>ClCCl>[CH2:12]([C:16]1[CH:21]([C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])[CH2:20][CH2:19][CH2:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC1=CCCCC1
Reactant: C/C=C/C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: C/C=C/C(=O)C1CCCC=C1CC(C)C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
At −70° C., a solution of tin tetrachloride (533 ml, 4.54 mol, 1.4 eq.) in dichloromethane (2.5 l) was treated with crotonyl chloride (350 ml, 90%, 3.24 mol, 1.0 eq.). The resulting solution was stirred for 30 min. and treated within 1.5 h with a solution of 1-isobutylcyclohex-1-ene (448 g, 3.24 mol) in dichloromethane (400 ml). The resulting mixture was stirred for 1 h at −70° C. and poured into ice/H2O. The org. phase was first washed with concentrated NaOH then with H2O, dried (MgSO4), and the solvent evaporated. Short-path Vigreux-distillation (0.15 mbar, bath temperature: 160° C.) of the crude product (592 g) gave a fraction (495 g, boiling range: 90-130° C.) that was redistilled using again a short-path Vigreux-column (0.11 mbar, bath temperature: 160° C.) to give (E)-1-(2-isobutylcyclohex-2-enyl)but-2-en-1-one (202 g, 30%). Boiling point: 120° C. (0.11 mbar).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[N:8]=[CH:9]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[N:8]=[CH:9]2
Reactant: O=C(O)c1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2cnc(C(=O)O)cc12
Reaction time: 5 h
Yield: 92.2 %

Procedure:
5-Nitroisoquinoline-3-carboxylic acid (44 g) is dissolved in methanol (3 liters), and a catalyst consisting of palladium-on-carbon (3/97 by weight; 15 g) is added. The mixture is hydrogenated at atmospheric pressure, at a temperature between 20° and 25° C. After stirring for 5 hours, the volume of hydrogen absorbed is 13.9 liters. The mixture is filtered through diatomaceous silica and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. to yield 5-aminoisoquinoline-3-carboxylic acid (35 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:12][N:11]3[C:24]=2[I:25])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][N:21]([C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH2:20][CH2:19]4)=[N:12][N:11]3[C:24]=2[I:25])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1c(N2CCNCC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Yield: 78.4 %

Procedure:
A solution of 0.70 g (1.55 mmol) of 2-(4-fluorophenyl)-3-iodo-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazine and 19 mg (0.16 mmol) of dimethylaminopyridine in 10 mL of tetrahydrofuran is treated with 0.41 g (1.9 mmol) of di-tert-butyl carbonate for 1 hour. The solvent is then evaporated off and the solid obtained is recrystallized from acetonitrile. 0.67 g of product is thus isolated after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[N:32]([CH3:45])[N:33]=[C:34]3[C:39]=2[CH:38]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]3[Cl:44])[CH:9]([C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[N:32]([CH3:45])[N:33]=[C:34]3[C:39]=2[CH:38]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:36]=[C:35]3[Cl:44])[CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:29][CH:30]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the faster-eluting enantiomer of the product from Step B (4 mg, 0.006 mmol) in DCM (1 mL) was added TFA (1 mL, 13 mmol), and the solution was stirred for 30 minutes at RT. The solution was concentrated, then the residue was purified by reverse phase HPLC eluting with acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the enantiopure title compound as a white solid. This was the most potent glucagon receptor antagonist of the four stereoisomeric compounds. 1H NMR (600 MHz, CD3OD): δ 8.44 (s, 1 H); 7.60 (d, J=8.3 Hz, 2H); 7.52 (d, J=8.0 Hz, 2H); 7.40 (d, J=8.3 Hz, 2H); 7.39 (s, 1H); 7.32 (d, J=8.0 Hz, 2H); 5.02 (d, J=11.9 Hz, 1H); 4.07 (s, 3H); 4.02 (td, J=11.3, 3.4 Hz, 1H); 3.51 (t, J=7.0 Hz, 2H); 2.54 (t, J=7.0 Hz, 2H); 1.76-1.61 (m, 2H); 1.19-1.02 (m, 2H); 0.78 (t, J=7.3 Hz, 3H); LC1 2.44 min. (M+H)− 606.
Reaction SMILES: [CH3:1][N:2]([N:15]=[O:16])[C:3]([NH:5][C@@H:6]1[O:14][CH2:13][C@@H:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[OH:8])=[O:4].C(O[C:21](=[O:23])[CH3:22])(=O)C>N1C=CC=CC=1>[CH3:1][N:2]([N:15]=[O:16])[C:3]([NH:5][C@@H:6]1[O:14][CH2:13][C@@H:11]([O:12][C:21](=[O:23])[CH3:22])[C@H:9]([O:10][C:9](=[O:10])[CH3:11])[C@H:7]1[O:8][C:7](=[O:8])[CH3:6])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(N=O)C(=O)N[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1NC(=O)N(C)N=O
Yield: 87 %

Procedure:
1-methyl-1-nitroso-3-(β-D-xylopyranosyl)urea (110 mg) was dissolved in a mixture of pyridine (1 ml) and acetic anhydride (1 ml) and the resulting mixture was allowed to stand at room temperature for effecting the acetylation. The reaction mixture was then concentrated under a reduced pressure to give a crystalline residue which was then crystallized from ethanol, yielding the titled compound (147 mg). Yield 87.0%. mp. 127°-127° C. (with decomposition). [α]D20 -25.4° (c 0.7, chloroform).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1ccc(C)c2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 69.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4,7-dimethylbenzothiazole (91 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 111 mg (69%) of the title compound as an amorphous foam. FDMS: m/e=422. α[D]589 =+63.27 (c=0.95, chloroform).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[N:12]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13](=[O:15])[N:12]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(C(C)C)cc3)oc2=O)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1ccc(-c2nn(Cc3ccc(C(=O)O)cc3)c(=O)o2)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Methyl 4-{[5-(4-isopropylphenyl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl]methyl}benzoate (50 mg, 0.14 mmol) is refluxed with lithium iodide (0.19 g, 1.4 mmol) in pyridine (5 mL) for 48 h and the mixture is diluted with water (30 mL) after cooling to room temperature. The precipitate is collected by filtration, washed with dichloromethane and dried in the air to furnish the desired product 4-{[5-(4-isopropylphenyl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl]methyl}benzoic acid (31 mg, 66%), m.p. 217-219° C. 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.13 (d, 6H) 2.70-2.90 (m, 1H), 4.86 (s, 2H), 7.17 (d, 2H), 7.30 (d, 2H), 7.59 (d, 2H), 7.89 (d, 2H). MS (ES+): m/e 339.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH2:20]([C:11]1[S:10][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:8])=[CH:13][CH:12]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CI
Reactant: CC(C)(C)NS(=O)(=O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
N-tert-Butylthiophene-2-sulfonamide (10 g, 0.046 mol, see step (a) above) was dissolved in THF (85 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 76.9 mL, 0.12 mol) was added via a syringe. The reaction mixture was stirred at −78° C. for 30 min. and then at −40° C. for 2 h. Iodo-2-methylpropane (10.5 mL, 0.09 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with NH4Cl (aq.) and extracted with EtOAc. The combined organic phase was washed with brine and dried and concentrated in vacuo. The crude product was purified on column chromatography (hexanes:EtOAc (10:1)) to give the sub-title compound in 55% yield (7.0 g, 0.025 mol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)(=[O:3])[NH2:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([C:26]([F:28])([F:29])[F:27])[CH:18]=1)(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C(F)(F)F)c3)c2cc1C(N)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1C(N)=O
Yield: 107.9 %

Procedure:
After dissolving 6-carbamoyl-4-(3-trifluoromethyl-4-nitrophenoxy)-7-methoxyquinoline (0.60 g) in tetrahydrofuran (10 ml) and methanol (10 ml), the solution was subjected to catalytic reduction with palladium-carbon (600 mg) for 10 hours under a hydrogen atmosphere to obtain the title compound (0.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([NH:7][OH:8])=[NH:6].[CH3:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O.C1C=CC2N(O)N=NC=2C=1.N=C=N.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:19]([C:18]3[CH:22]=[CH:23][N:24]=[CH:25][C:17]=3[CH3:16])[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: Cc1cnccc1C(=O)O
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnccc1-c1nc(-c2ccc(OC(C)C)c(Cl)c2)no1
Temperature: 160 °C
Yield: 10.4 %

Procedure:
To a microwave vial charged with 3-chloro-N-hydroxy-4-isopropoxy-benzamidine (75 mg, 0.328 mmol), 3-methyl-isonicotinic acid (41 mg, 0.298 mmol), HOBt (46 mg, 0.298 mmol), PS-carbodiimide (720 mg, 0.894 mmol, loading 1.24 mmol/g) was added acetonitrile (3.5 mL) and diisopropylethylamine (156 μL, 0.894 mmol). The reaction vial was capped and heated at about 160° C. for about 30 minutes in a Biotage microwave. The reaction mixture was filtered and the resin was washed with acetonitrile (4 mL). Filtrate was concentrated to dryness. The crude product was purified via reverse phase HPLC (30-90% acetonitrile, 30 minute ramp) to give 10.2 mg (10%) of 4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21]C(O)CO.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1
Reactant: COc1cscc1OC
Reactant: COCCOCCOCCOCC(O)CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCOCCOCCOCC1COc2cscc2O1
Temperature: 100 °C

Procedure:
A transetherification reaction between 3,4-dimethoxythiophene (12.9 g, 89 mmol) and {2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxymethyl}-1,2-ethanediol (24.5 g) in toluene (150 mL) was performed by heating (at 100° C.) a mixture of these compounds under a continuous nitrogen flow for 24 h. Subsequently, the reaction mixture was poured into methylene chloride (200 mL) and the organic phase was washed a 1M aqueous solution of sodium hydrogen carbonate, a concentrated aqueous solution of sodium chloride, dried with anhydrous magnesium sulphate and concentrated. This resulted in a viscous oil. Pure 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxymethyl}-2,3-dihydro-thieno[3,4-b][1,4]dioxine was finally obtained by vacuum distillation.
Reaction SMILES: N#N.C(OC([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1
Reactant: O=C(N[C@H]1CC[C@@H](CO)CC1)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: N[C@H]1CC[C@@H](CO)CC1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of cis-4-benzyloxycarbonylaminocyclohexane-methanol (235 mg, 0.89 mmol) in MeOH (5 mL) was hydrogenated in the presence of Pd/C (10%) at rt until completion of the reaction. The mixture was then filtered and concentrated under reduced pressure. The title compound was obtained as a colorless oil. LC-MS-conditions 07: tR=0.12 min; [M+H]+=130.26.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:15][CH:14]([NH:16]C(=O)OC(C)(C)C)[CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH:14]([NH2:16])[CH2:15]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Yield: 95.2 %

Procedure:
tert-Butyl {1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}carbamate (0.85 g, 2.42 mmol) was dissolved in DCM (4 mL) and TFA (3 mL) and stirred at rt for 1 h. The mixture was concentrated and redissolved in EtOAc, washed with saturated aqueous K2CO3. The organic layer was dried with Na2SO4, filtered and evaporated affording the title compound (0.58 g, 95.1%). 1H NMR (500 MHz, CDCl3): δ 1.65 (bs, 2H), 3.91-3.98 (m, 3H), 4.57-4.61 (m, 2H), 7.58 (s, 1H), 8.26 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 43.68, 63.02, 115.38, 116.90 (q, JC-F=33.2 Hz), 123.91 (q, JC-F=270.9 Hz), 134.95, 143.76, 157.56; Mass Spectrum: M+H+ 252.
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH:2]([CH3:4])[CH3:3].[Br:10]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[Br:10][C:7]1[S:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:9][CH:8]=1
Reactant: CC(C)Cc1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)Cc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 2-isobutylthiazole (600 mg, 4.25 mmol) in DMF (2 mL) was added N-bromosuccinimide (1.134 g, 6.37 mmol). The mixture was stirred at room temperature for 3 hours then subjected to flash column chromatography using 10% ethyl acetate/hexane to give a yellow oil (815.2 mg, 87% yield). LCMS (Conditions C): Tr 3.51 min; (M+H)': 219.90 (100%), 221.90 (100%).
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])=O.[Na+].[CH:12]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:41](=[O:43])C)[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:44]=[CH:45][C:46]([Cl:48])=[CH:47][C:19]1=2)=[O:17])([CH3:14])[CH3:13]>C(O)=O>[CH:12]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH:41]=[O:43])[C:20]2[CH:44]=[CH:45][C:46]([Cl:48])=[CH:47][C:19]1=2)=[O:17])([CH3:14])[CH3:13]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)OC(=O)N1CCCC(N(C=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
Add acetic anhydride (0.22 mL, 2.34 mmol) and sodium formate (26 mg, 0.39 mmol) to a solution of 5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (see example 3) (40 mg, 0.078 mmol) in formic acid (0.5 mL) and stir at room temperature for 16 h. Chromatograph the residue over silica cartridge, eluting with hexanes/ethyl acetate (5:1), to afford the title compound (27 mg, 64%). 1H NMR (DMSO-d6, 300 MHz, 100° C.) δ 1.14 (d, J=6.5 Hz, 6H), 1.63-2.05 (m, 2H), 3.43 (m, 1H), 3.63 (m, 1H), 4.56-4.61 (m, 1H), 4.70-4.72 (m, 1H), 4.77-4.89 (m, 2H) 7.09 (d, J=8.3 Hz, 1H), 7.23-7.26 (m, 2H), 7.80-7.86 (m, 3H), 8.46 (s, 1H). MS (ES+): 537 (M+H).