Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[I:13]Cl.O>C(O)(=O)C.II>[I:13][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: ClI
Reactant: COc1cccc(CC(=O)O)c1
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(I)c(CC(=O)O)c1
Yield: 64.7 %

Procedure:
A solution of 45 g (0.27 mole) of 3-methoxybenzeneacetic acid, 52.6 g (0.32 mole) of iodine monochloride and 1 g of iodine was allowed to stand in 500 ml of glacial acetic acid for six days at room temperature. The reaction was poured into water and the solid collected. It was recrystallized from toluene to give 51 g of crystalline 2-iodo-5-methoxybenzeneacetic acid, mp 133.5°-134.5° C. (65% yield).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N+:25]=2[O-])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:3][NH:4][C:5]1([CH3:9])[CH2:8][O:7][CH2:6]1>C(O)C.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N:25]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:3][NH:4][C:5]1([CH3:9])[CH2:8][O:7][CH2:6]1
Reactant: CC(C)CN(c1ccc(C(C)C)c[n+]1[O-])S(=O)(=O)c1ccc(C(O)CNC2(C)COC2)cc1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CCO
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(C(O)CNC2(C)COC2)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-(1-hydroxy-2-((3-methyloxetan-3-yl)amino)ethyl)-N-isobutylphenylsulfonamido)-5-isopropylpyridine 1-oxide (71.9 mg, 0.151 mmol), in ethanol (1 mL) stirred in air at 20° C., was added molybdenum hexacarbonyl (39.7 mg, 0.151 mmol). The reaction was heated by microwaves to 100° C. for 10 minutes. After cooling, the reaction mixture was filtered and solids washed with ethanol (5 mL) and dichloromethane (5 mL). The combined filtrate was evaporated in vacuo and the crude sample purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the title product, 7.5 mg. LCMS (2 min, formic) Rt 0.91 min, m/z (ES+) 462 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].I[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc2c(ccn2-c2ccccc2)c1
Temperature: 125 °C
Reaction time: 10 h
Yield: 62.7 %

Procedure:
To a mixture of 5-methoxyindole (1.00 g, 6.79 mmol), copper(I) iodide (129 mg, 0.68 mmol), L-proline (156 mg, 1.36 mmol) and potassium carbonate (1.88 g, 13.6 mmol) in DMSO (7.5 ml) was added iodobenzene (0.76 ml, 6.79 mmol). The reaction mixture was stirred for 10 h at 125° C. in a microwave reactor. The mixture was then quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:15). 951 mg of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: Fc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c(F)c1

Procedure:
A mixture of 1-(2,4-difluorophenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,4-difluorophenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].CN(C=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23]Cl>C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[C:2]([F:1])([F:10])[F:11]
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cccc2C(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
2-(Trifluoroacetyl)-1H-pyrrole (0.97 g) was added to DMF solution (10 ml) of 60% sodium hydride (0.16 g) and the mixture was stirred at room temperature for 30 minutes. 3-Methyl-4-nitrobenzyl chloride (1.0 g) was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-2-(trifluoroacetyl)-1H-pyrrole (1.53 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)(=O)=O.[Cl:22][C:23]1[C:24]([F:43])=[C:25]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37](O)[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O.O.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([F:43])=[C:25]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:11][CH:12]4[CH2:21][CH2:20][C:15]5([O:19][CH2:18][CH2:17][O:16]5)[CH2:14][CH2:13]4)[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
12.5 g potassium carbonate and 16 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan (cf. for example Journal of Medicinal Chemistry (1992), 35(12), 2243-7) in 125 ml dimethylformamide are added at 50° C. to 18.1 g 4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline (cf. for example Bioorganic & Medicinal Chemistry Letters (2006), 16(18), 4908-4912) and the mixture is stirred for 18 hours at 80° C. Another 4.7 g potassium carbonate and 4.0 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added and the mixture is stirred for a further 7 hours at 80° C. The reaction mixture is cooled, diluted with water and ethyl acetate and the precipitate formed is suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[N:6][C:5]2=[C:14]([C:16]([OH:18])=O)[CH:15]=1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[C@H:22]([NH:21][C:16]([C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[N:6][C:5]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3cccs3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc(Cl)cc2oc(-c3cccs3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A mixture of 6-chloro-2-(thiophen-2-yl)benzo[d]oxazole-4-carboxylic acid (70 mg, 0.25 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (50 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.00 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (s) —N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide (30 mg, 31%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.40 (d, J=7.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.94 (dd, J=4.0, 1.5 Hz, 1H), 7.67-7.65 (m, 2H), 7.26-7.23 (m, 1H), 4.30-4.26 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.15-2.85 (m, 4H), 2.77 (dd, J=14.5, 3.5 Hz, 1H), 2.15-2.05 (m, 2H), 1.78-1.70 (m, 2H), 1.65-1.53 (m, 1H); MS (ESI+) m/z 388 (M+H); HPLC>99% (AUC), tR=13.84 min.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].N[C:14]1[CH:19]=CC=CN=1>C(#N)C>[N:10]1[CH:11]=[CH:12][CH:19]=[CH:14][C:9]=1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccn1
Solvent: CC#N
Product: S=C(Nc1ccccn1)n1ccnc1
Yield: 133.2 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-aminopyridine (4.75 g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 72 h. The resulting solution was evaporated to a black oil and triturated with hexane. The remaining oily residue was placed under vacuum to provide 13.6 g of crude titled product as a black solid:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([CH3:3])[CH3:2].[P:11](Cl)([Cl:14])([Cl:13])=[S:12].N1C=CC=CC=1>ClC=C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[P:11]([Cl:14])([Cl:13])=[S:12])([CH3:3])[CH3:2]
Reactant: S=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccccc1O
Solvent: c1ccncc1
Solvent: ClC=C(Cl)Cl
Product: CC(C)c1ccccc1P(=S)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-iso-propylphenol (10.0 g, 73.4 mmol) in trichloroethylene (600 mL) is added dropwise to a 0°-4° C. mixture of thiophosphoryl chloride (18.63 g, 110 mmol) and anhydrous pyridine (8.70 g, 110 mmol) in trichloroethylene (250 mL) over a 1 hour period under a nitrogen atmosphere. The resultant reaction mixture is stirred at 0°-4° C. for 2 hours, is warmed to room temperature and then is stirred at room temperature for 12 hours. A white solid gradually precipitates. The white solid is filtered from the reaction mixture. The resultant reaction mixture is concentrated in vacuo to a residue. Successive aliquots of toluene (200 mL) are added to the residue and then separately evaporated in vacuo to give (2-iso-propylphenyl)-thiophosphoryl dichloride which can be used directly without further purification as the starting material for Example 27.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH:6]([CH2:8][CH3:9])[CH3:7].[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]=[S:22]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]1[N:5]([CH:6]([CH2:8][CH3:9])[CH3:7])[CH2:4][CH2:3][S:22]1
Reactant: CCC(C)[NH2+]CCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: CCC(C)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Butylamine was converted to N-(2-hydroxyethyl)-N-(2-butyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(2-butyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-butyl)-1,3-thiazolidine.
Reaction SMILES: N1C=CC=CC1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]1[NH:20][C:21]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)=[C:22]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:23]([C:30]2[N:31]=[N:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:35]=2)[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:13])([CH3:10])([CH3:9])[CH3:8].[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([C:30]2[N:31]=[N:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:35]=2)[C:22]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:21]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)[N:20]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)C1=C(Cc2ccc(F)cc2)NC([C@@H]2CCCN2C(=O)OC(C)(C)C)=C(C(=O)OCC)C1c1ccc(C(=O)OCC)nn1
Agent: C1=CCNC=C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(-c2c(C(=O)OCC)c(Cc3ccc(F)cc3)nc([C@@H]3CCCN3C(=O)OC(C)(C)C)c2C(=O)OCC)nn1
Reaction time: 0.08 h

Procedure:
To the dihydropyridine (D, diethyl 2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-4-[6-(ethoxycarbonyl)-3-pyridazinyl]-6-(4-fluorobenzyl)-1,4-dihydro-3,5-pyridinedicarboxylate, 265 mg, 0.41 mmol} in 9 ml acetonitrile, ammonium cerium nitrate (445 mg, 0.82 mmol) in 1.8 ml water was added. The reaction mixture was stirred for 5 minutes. Ten (10) ml water was added and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent provided 260 mg orange foam which was carried to the next step without further purification. ESI-MS m/z 651 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:19]=[CH:18][CH:17]=[C:8](C(C2C=CC=CC=2)=O)[CH:7]=1)[CH3:5])=[O:3]>C1COCC1>[C:6]1([CH:4]([CH3:5])[C:2]([OH:3])=[O:1])[CH:19]=[CH:18][CH:17]=[CH:8][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccccc1

Procedure:
Working as in Example 35, with 0.389 g of phase, 0.18 g of LiOH monohydrate, 60 ml of THF and hydrolysis for 48 h, 0.31 g of α-phenylpropionic acid and ketoprofen is obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH3:25]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[CH3:25])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Cc1ccc(F)cc1Br
Product: CCSc1ncc(C(=O)c2cc(F)ccc2C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-fluorotoluene (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([CH:10]1[CH2:19][CH:18]2[CH:13]([CH:14]=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17]2)[CH:12]([C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[NH:11]1)=[O:9].CCN(CC)CC>C(Cl)Cl>[CH3:6][O:7][C:8]([CH:10]1[CH2:19][CH:18]2[CH:13]([CH:14]=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17]2)[CH:12]([C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[N:11]1[C:3](=[O:4])[CH2:2][Cl:1])=[O:9]
Reactant: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.23 mL), 2.88 mmol) was added dropwise to a mixture of Intermediate 7 (0.82 g, 2.21 mmol) and Et3N (0.71 mL, 5.09 mmol) in CH2Cl2 (15 mL) at 0° C. under a nitrogen blanket. The resulting mixture was warmed to room temperature and stirred for about 0.5 hour. The reaction was quenched with 1 N HCl (2 mL), and diluted with CH2Cl2 (50 mL) and-water (10 mL). The layers were separated and the organic was washed with saturated NaCl and dried over anhydrous Na2SO4. Filtration and concentration in vacuo afforded Intermediate 8 (1.5 g), which was used without further purification. TLC Rf (10% EtOAc/CH2Cl2)=0.55; MS (API) m/z 448 (M+H), 472 (M+Na).
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.I[CH2:14][CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:18].O>CN(C)C=O.C(N(CC)CC)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]([CH2:16][CH2:15][CH2:14][N:9]2[CH2:8][CH2:7][C:6]3([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]3)[CH2:11][CH2:10]2)=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: O=C1COC2(CCNCC2)CN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC2(CCN(CCCC(=O)c3ccc(F)cc3)CC2)CN1

Procedure:
A solution of 2.5 g of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one and 5 ml of 4-iodo-p-fluorobutyrophenone in 60 ml of dimethylformamide and 10 ml of triethylamine was heated at 60° C. for 10 hours. The mixture was poured into water, extracted with methylene chloride, and the methylene chloride layer was extracted with aqueous 5% HCl. Basification of the aqueous extract with ammonium hydroxide and extraction with methylene chloride followed by evaporation gave a residue which was crystallized from ethyl acetate-hexane to give 9-[3-(4-fluorobenzoyl)propyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, m.p. 117°-118° C. The HCl salt of 9-[3-(4-fluorobenzoyl)propyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one was prepared by dissolving the base in methanolic HCl and precipitating with ether, m.p. 225°-230° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[O:19][C:18]([CH:20]=[CH:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[O:1]([CH2:8][CH2:9][CH2:10][N:26]1[CH:25]=[CH:24][N:23]=[C:22]1[CH:21]=[CH:20][C:18]1[O:19][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Product: O=[N+]([O-])c1ccc(C=Cc2nccn2CCCOc2ccccc2)o1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 3-phenoxypropyl bromide and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. The resulting orange product after recrystallization from ethanol-water melted at 85°-86°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH2:45][O:46]C>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][O:46][CH3:45])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: COCCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COCCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-methoxyethane and isolated as light-yellow gum (4.5 mg, 32%). MS (m/e): 341.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH3:24]O>>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([O:17][CH3:24])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CO
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
15 g (0.06 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid, 150 ml of methanol and 1.6 ml of concentrated sulfuric acid were introduced into a round-bottomed flask. The mixture was heated at reflux for 4 hours, the reaction medium evaporated, taken up in water, and extracted with ethyl acetate. The organic phase was decanted off and dried over magnesium sulfate. 15.9 g (99%) of the expected ester of melting point 83°-85° C. were recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=1)#[N:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30]([C:26]3[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[CH:28][N:27]=3)=[O:31])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccnc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(C#N)ccn3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 1 h, 70 mg, 236 μmol, Eq: 1.00), 4-cyanopicolinic acid (CAS 640296-19-1, 45.5 mg, 307 μmol, Eq: 1.3) and HBTU (134 mg, 354 μmol, Eq: 1.5) were dissolved in DMF (1.25 ml), treated with N-Methylmorpholin (71.7 mg, 77.9 μl, 709 μmol, Eq: 3) and stirred at r.t. for 17 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered off and concentrated under vacuo. The solid residue was diluted with a small volume of MeOH, and filtered, leading to 64 mg of a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N2C[C@H](O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis-4-hydroxy-D-proline (0.308 g, 2.67 mmol) is dissolved in 16 mL of a 1:1 mixture of water and p-dioxane and then triethyl amine (0.819 mL, 5.89 mmol), 4-butoxyphenylsulfonyl chloride (0.700 g, 2.81 mmol), and 4-dimethylaminopyridine (0.033 g, 0.268 mmol) are added. The resulting solution is stirred at room temperature overnight. The reaction is then washed with sodium bicarbonate and extracted once with ether. The water layer is acidified with 1N HCl to pH=2 and extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, dried (MgSO4), filtered and evaporated to give the crude compound. Cl+ MS: m/z (rel intensity) 361 (M+ +H, 40).