Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[F:24][CH:25]([F:51])[O:26][C:27]1[CH:50]=[CH:49][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([C:37]3[S:38][C:39]([C:43]([O:45]CC)=[O:44])=[C:40]([CH3:42])[N:41]=3)[C:33]2=[O:48])=[CH:29][CH:28]=1>>[F:51][CH:25]([F:24])[O:26][C:27]1[CH:50]=[CH:49][C:30]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([C:37]3[S:38][C:39]([C:43]([OH:45])=[O:44])=[C:40]([CH3:42])[N:41]=3)[C:33]2=[O:48])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)O
Yield: 88 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(4-(difluoromethoxy)benzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 88% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.43-6.94 (m, 5H), 4.39 (s, 2H), 3.97 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H), 2.46 (s, 3H): MS (ES+) m/z 384.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1.CCO.O>[Fe].CC(O)=O>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH2:8])[N:5]=2)=[CH:15][CH:14]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Nc2ccc(N)cc2)nc(N)n1

Procedure:
To a refluxing suspension of amine E2 (5.46 g, 0.02 mol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (4.97 g, 0.09 mol) and AcOH (2 mL, 2% v/v), and the resulting dark brown suspension was refluxed for ˜14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and solvent was removed under reduced pressure. The resulting residue was extracted with hot water, and the resulting aqueous suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue extracted again with hot water. The resulting aqueous suspension was filtered through a pad of Celite. Solvent was removed to afford amine E3 as a brown-white crystalline solid (4.85 g, quantitative). 1H NMR [CD3)2SO]: 2.01 [s, 3H, ArCH3], 5.68 [s, 1H, ArNHAr], 5.88 [br s, 2H, ArNH2], 6.51 [ddd, J=9.67, 4.85, 2.94 Hz, 2H, ArH], 7.14 [d, J=8.52 Hz, 2H, ArH], 8.35 [s, 1H, ArH]. LCMS (APCl+): 216 (100%).
Reaction SMILES: [N+:1]([C:4]12[CH2:13][N:8]3[CH2:9][N:10]([CH2:12][N:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([O-])=O.[H][H]>[Rh].C.C(O)C>[NH2:1][C:4]12[CH2:13][N:8]3[CH2:7][N:6]([CH2:12][N:10]([CH2:9]3)[CH2:11]1)[CH2:5]2
Reactant: O=[N+]([O-])C12CN3CN(CN(C3)C1)C2
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: NC12CN3CN(CN(C3)C1)C2

Procedure:
7-Nitro-1,3,5-triazaadamantane (46.1 g., 0.25 mole), 175 ml. of 95% ethanol and 8.0 g. of 5% rhodium-charcoal catalyst were shaken with hydrogen in a Parr apparatus at 25° until hydrogen uptake ceased (13 hours). (The reaction bottle was refilled with hydrogen at intervals as required to keep the hydrogen pressure between 25-50 psi.) The reaction mixture was filtered with suction through Celite and the collected catalyst washed thoroughly with ethanol. The filtrate was concentrated to dryness under reduced pressure and the solid residue, after being ground to a powder, was pumped at 25° and 0.1 mm for 12 hours to remove traces of volatiles to yield 38.6 g. (99.5%) of high purity 2, m.p. 216°-219°. The product may be recrystallized from benzene (80% recovery) to yield long needles, m.p. 214°-217°; nmr (deuterium oxide): δ 4.70 (2, s, OH), 4.39, 3.97 (6, ABq, J = 12 Hz; 2,4,9 CH2), 3.17 (6, s, 6,8,10 CH2); TMS external standard.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 36 h
Yield: 86.5 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (330 mg, 2.64 mmol) was dissolved in anhydrous DMF (8 mL). Solid K2CO3 (547 mg, 3.96 mmol) was added, followed by the addition of 1-chloro-4-(chloromethyl)benzene (638 mg, 3.96 mmol). The reaction was permitted to stir at 60° C. for 36 h, at which time the reaction was allowed to cool to rt. Water was added and the resulting precipitate was isolated over a filter, and dried under high vacuum overnight to give 570 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC([C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=CC=1>>[O:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: O=C(Cc1ccccc1)c1ccc(N2CCOCC2)cc1
Yield: 36 %

Procedure:
Prepared from 4-(4-bromophenyl)morpholine following the procedure described in Intermediate 14, where the crude product was purified by column chromatography (PE: EtOAc=5:1) to afford Intermediate 25 (280 mg, yield 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11]1[S:10][CH2:16][C:14](=[O:15])[N:13]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccccc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 10.4 %

Procedure:
To a suspension of 2-chloro-benzylamine (7.88 g, 55 mmol) and Rhodanine (6.65 g, 50 mmol) in acetonitrile (150 mL) was added DIPEA (19.15 mL, 110 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (13.5 g, 50 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (1 L) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). After shaking, lot of solids formed which was collected by filtration to obtain 1.25 g of the desired product. Then, the two layers were separated and the ethyl acetate layer was washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the ethyl acetate solution was removed partially and the remaining solution was stored in the refrigerator. Then, the precipitated solids were collected by filtration to afford 2.67 g of the desired product. Then, the aqueous layer was again extracted with dichloromethane (2×150 mL). The combined dichloromethane extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to obtain 4.2 g (total product 8.12 g, 67.5% yield) of 2-(2-chloro-benzylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C10H9ClN2OS (M+) 240.0124, found 240.0122.
Reaction SMILES: [Br:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4].[NH3:13]>>[BrH:1].[NH2:13][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4]
Reactant: N
Reactant: CC1(C)NC(=O)CN1C(=O)CBr
Product: Br
Product: CC1(C)NC(=O)CN1C(=O)CN

Procedure:
A solution of 1-(2-bromoacetyl)-2,2-dimethyl-4-imidazolidinone (2 g) in 33% ammonia solution (80 ml) was stirred at room temperature overnight. After evaporation under reduced pressure, the residue was dissolved in dry ethanol and evaporated again to give 1-(2-aminoacetyl)-2,2-dimethyl-4-imidazolidinone hydrobromide as a white deliquescent powder (Rf 0.33, n-butanol/water/acetic acid 6:2:2, silica gel plates). The latter compound can also be prepared using the chloroacetyl derivative in a similar procedure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]([C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21])([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:25]
Reactant: COC(=O)Cc1ccccc1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
A solution of phenyl-acetic acid methyl ester (4 g, 27.3 mmol) and 4-bromo-1-fluoro-2-nitro-benzene (5 g, 22.7 mmol) in DMF (30 mL) was slowly added to a suspension of NaH (60% in mineral oil, 3 g, 77.1 mmol) in DMF (80 mL) at 0° C. under N2. The reaction was then stirred for 3 h at room temperature. MeI (5.6 mL, 91 mmol) was then added and the reaction was stirred overnight at the same temperature. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. Chromatography (10% EtOAc in 40-60 petroleum ether) gave the title compound (2.6 g) as an orange semi-solid. 1H NMR (DMSO-d6): 8.21-8.14 (1H, m), 7.86-7.77 (1H, m), 7.44-7.36 (5H, m), 6.84 (1H, d), 3.53 (3H, s), 2.06 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C1(C)C(C)=CC=CC=1>O>[C:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]([CH3:12])[C:7]1=[O:11])(=[O:15])[CH3:14]
Reactant: CC1C(=O)Nc2cc(Br)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=O)N1C(=O)C(C)c2ccc(Br)cc21

Procedure:
To 6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one (11.2 g) were added acetic anhydride (12 ml) and xylene (120 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (9.5 g) as a red solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O[N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:38]=[C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36](=[O:37])[N:28]1[O:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
Diethyl azodicarboxylate (17.4 g, 100 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (7.50 g, 37.3 mmol), 2-hydroxyisoindoline-1,3-dione (6.08 g, 37.3 mmol) and triphenylphosphine (19.6 g, 74.6 mmol) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 5/95 to 12.5/87.5) to give tert-butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate (5.81 g, 45%) as a white solid: LCMS: 247 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl.[CH2:27]([NH2:29])[CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:29][CH2:27][CH3:28])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCN
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Agent: Cl
Product: CCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and ethylamine hydrochloride as an off-white solid (61%). MS 374 (MH+).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].C(O)[CH2:14][OH:15].[CH3:17][OH:18]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[OH:15][CH2:14][CH2:12][O:11][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH2:17][OH:18])=[O:7]
Reactant: COC(=O)CCCCC(=O)OC
Reactant: CO
Reactant: OCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: O=C(CCCCC(=O)OCCO)OCCO
Temperature: 190 °C

Procedure:
A 1-liter glass flask equipped with a stirrer, thermometer, gas inlet, and distillation outlet was charged with 174.2 g (1.00 mole) of dimethyl adipate, 198.3 g (2.20 moles) of ethylene glycol, and a small amount of tetrabutyl titanate as a catalyst. The mixture in the flask was purged with nitrogen, heated to 190° C., and reacted at this temperature for 1 hour. As the reaction proceeded, bis(2-hydroxyethyl)adipate was produced with the distillation of methanol from the flask.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][N:60]=[C:59]([N:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[CH:58]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:66]3[CH2:67][CH2:68][N:63]([C:59]4[CH:58]=[C:57]([O:56][CH3:55])[CH:62]=[CH:61][N:60]=4)[CH2:64][CH2:65]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: COc1ccnc(N2CCNCC2)c1
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: COc1ccnc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 39 mg TBTU and 53 μL DIPEA were added to this solution and the mixture was stirred for a few minutes at RT. Then 24 mg 1-(4-methoxy-pyridin-2-yl)-piperazine was added. The mixture was stirred 1 h at RT. The reaction-solution was evaporated and the residue was purified by HPLC to give 30 mg of the desired compound. Rt: 1.68 (method C), (M+H)+: 491
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:15][C:14]([F:17])([F:16])[S:11]([O:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:12])=[O:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(Oc1ccc2c(c1)CCC2)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: Oc1ccc2c(c1)CCC2

Procedure:
The title compound, MS: m/e=244.1 (M+) was obtained as a light yellow oil (96% yield) using trifluoro-methanesulfonic acid indan-5-yl ester obtained in turn from indan-5-ol by treatment with trifluoro-methanesulfonic anhydride, DMAP and triethylamine in CH2Cl2 at −70° C. to 20° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:9][CH:24]=[N:23][CH:22]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Yield: 95.3 %

Procedure:
A mixture of 4-nitro benzaldehyde (500 mg, 3.31 mmol), tosylmethyl isocyanide (640 mg, 3.31 mmol) and potassium carbonate (1.37 g, 9.9 mmol) were heated to reflux in methanol (10 ml) for 2 hr. Evaporation of the solvent yielded a residue, which was diluted with water and extracted into ethyl acetate. The organic layer was washed with water and brine, dried and concentrated under reduced pressure to yield 5-(4-nitro-phenyl)-oxazole (600 mg, 95%) as solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:6]1([C:4]2[C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:1][C:18]3[N:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Product: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 190 °C
Yield: 26.9 %

Procedure:
A mixture of 19.7 g (0.1 mole) of 2-aminobenzophenone and 15.0 g (0.12 mole) of 3-amino-2-chloropyridine was heated under nitrogen atmosphere at 190° C. for 1.75 hr. The mixture was cooled to room temperature and partitioned between 3N aqueous sodium hydroxide and methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 32.7 g, was dissolved in benzene and chromatographed on a column of florisil packed in benzene, eluting with benzene and 1-2% acetone-benzene mixtures. After evaporation, the solid was crystallized from benzene to give 7.3 g product; m.p. 106°-108° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:20][CH3:21])[C:14]=1[C:15](OCC)=[O:16])[CH3:8]>C1COCC1>[CH2:20]([C:13]1[CH:12]=[N:11][CH:10]=[C:9]([CH2:7][CH3:8])[C:14]=1[CH2:15][OH:16])[CH3:21]
Reactant: CCOC(=O)c1c(CC)cncc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(CC)c1CO
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a suspension of LAH (0.805 g, 21.22 mmol) in anhydrous THF (20 mL) at 0° C. was added a dropwise a solution of ethyl 3,5-diethylpyridine-4-carboxylate (2.20 g, 10.61 mmol) in THF (30 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH solution and then diluted with water. Ethyl acetate was added, the mixture was stirred for 10 minutes, and the precipitated white solid was filtered off. The solid was washed with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to provide (3,5-diethylpyridin-4-yl)methanol as a thick oil (1.50 g, 86% yield) which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 1.15 (t, 611), 2.70 (q, 4H), 4.50 (s, 2H), 5.06 (bs, 1H), 8.22 (s, 2H), M+208.5; M+166.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH2:17]([C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:18].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:27]2[CH2:28][CH2:29][N:24]([C:22]3[S:23][C:19]([CH2:17][CH3:18])=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:21]=3)[CH2:25][CH2:26]2)=[O:16])[O:4][N:3]=1
Reactant: CCc1sc(N2CCNCC2)nc1-c1ccccc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(N2CCN(C(=O)Nc3onc(C)c3C)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 35.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (231 mg, 0.805 mmol), 1-(5-ethyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.732 mmol) and diisopropylethylamine (0.255 ml, 1.46 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (106 mg, 35.3%) as a solid.
Reaction SMILES: C(N(CC)CC)C.C1(O[C:15](=[O:34])[NH:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[CH:21][N:20]3[CH:33]=2)C=CC=CC=1.Cl.[CH:36]([N:39]1[N:43]=[N:42][C:41]([CH2:44][CH2:45][NH2:46])=[N:40]1)([CH3:38])[CH3:37].O>CN1C(=O)CCC1>[CH:36]([N:39]1[N:43]=[N:42][C:41]([CH2:44][CH2:45][NH:46][C:15]([NH:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[CH:21][N:20]3[CH:33]=2)=[O:34])=[N:40]1)([CH3:38])[CH3:37]
Reactant: CC(C)n1nnc(CCN)n1
Reactant: COc1ccc(-c2ccc3nc(NC(=O)Oc4ccccc4)cn3c2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2ccc3nc(NC(=O)NCCc4nnn(C(C)C)n4)cn3c2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.54 ml, 3.26 mmol) is added to a stirred mixture of [6-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a]pyridin-2-yl]carbamic acid phenyl ester (Intermediate C) (0.587 g, 1.63 mmol) and 2-(2-isopropyl-2H-tetrazol-5-yl)-ethylamine hydrochloride (Intermediate D1)(0.275 g, 1.96 mmol) in NMP (5 ml). The resulting mixture is stirred at 80° C. for 2 hours and then allowed to cool to room temperature. Water (100 ml) is added and the resulting grey suspension is collected by filtration and dried in a vacuum oven to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]C)[N:7]=1.[CH:12]1([CH:15]2[NH:20][C:19](=O)[CH:18]([CH3:22])[NH:17][C:16]2=O)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([CH:10]2[CH2:11][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Cl:1][C:19]1[C:18]([CH3:22])=[N:17][CH:16]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:20]=1
Reactant: CCc1cnc(CC)c(Cl)n1
Reactant: CC1NC(=O)C(C2CC2)NC1=O
Product: Cc1cnc(C2CC2)c(Cl)n1
Product: Cc1ncc(C2CC2)nc1Cl

Procedure:
Following the procedure for the preparation of 3-chloro-2,5-diethylpyrazine but substituting 3-cyclopropyl-6-methylpiperazine-2,5-dione and making non-critical variations provided 3-chloro-2-cyclopropyl-5-methylpyrazine (A) and 3-chloro-5-cyclopropyl-2-methylpyrazine (B) as oils. Analytical data for 3-chloro-2-cyclopropyl-5-methylpyrazine (A): 1H NMR (CDCl3) δ 1.44, 2.35, 2.90, 3.07, 8.10; MS (ESI+) for C8H9N2Cl m/z 169 (M+H)+; Analytical data for 3-chloro-5-cyclopropyl-2-methylpyrazine (B): 1H NMR (CDCl3) δ 1.04, 2.00, 2.57, 8.10; MS (ESI+) for C8H9N2Cl m/z 169 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:12][C:13]2[CH:14]=[C:15]([F:28])[C:16]([F:27])=[C:17]([NH:19]C(=O)OC(C)(C)C)[CH:18]=2)[CH2:11][CH2:10][CH2:9]1.[Cl:29]CCl>>[ClH:29].[CH:8]1([O:12][C:13]2[CH:14]=[C:15]([F:28])[C:16]([F:27])=[C:17]([CH:18]=2)[NH2:19])[CH2:9][CH2:10][CH2:11]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1cc(OC2CCC2)cc(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Nc1cc(OC2CCC2)cc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (70 mL) was added to a solution of tert-butyl 5-cyclobutoxy-2,3-difluorophenylcarbamate (32 g, 107 mmol) in dichloromethane (320 mL), and the resulting solution stirred overnight at room temperature. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (500 mL). A solution of HCl (4 M in 1,4-dioxane, 120 mL) was slowly added with stirring. The resulting mixture was concentrated and poured into ethyl ether (480 mL). The resulting precipitate was filtered, and the filter cake was dried under reduced pressure to afford 5-cyclobutoxy-2,3-difluoroaniline hydrogen chloride (21 g, 89%) as a light yellow solid. MS (ESI, pos. ion) m/z 200 [M+H]+.